Aminoalcohol derivatives

ABSTRACT

The present invention relates to a compound formula [I]:  
                 
 
     wherein  
                 
 
     Y is bond, —O—(CH 2 ) n — (in which n is 1, 2, 3 or 4), etc.,  
     Z is cyano, tetrazolyl, etc.,  
     R 1  is hydrogen, lower alkyl, etc.,  
     R 2  is hydrogen or an amino protective group,  
     R 3  is hydrogen or lower alkyl,  
     R 4  is hydrogen or lower alkyl,  
     R 5  and R 8  are each independently hydrogen, halogen, hydroxy, lower alkyl, etc.,  
     R 6  is hydrogen, lower alkyl, etc.,  
     R 9  is hydrogen or lower alkyl, and  
     i is 1 or 2,  
     or a salt thereof. The compound [I] of the present invention and pharmaceutically acceptable salts thereof are useful for the prophylactic and/or the therapeutic treatment of pollakiurea or urinary incontinence.

FIELD OF THE INVENTION

[0001] This invention relates to new aminoalcohol derivatives and saltsthereof which are beta-3 (β₃) adrenergic receptor agonists and useful asa medicament.

BACKGROUND OF THE INVENTION

[0002] International Publications No. WO 90/06299, published Jun. 14,1990, describes derivatives of phenylethanolamines as having an effecton the metabolism, preferably reduction of the blood sugar level andbody fat, and International Publication No. WO 02/32897, published Apr.25, 2002, describes derivatives of alpha-aryl ethanolamines useful as β₃adrenergic receptor agonists.

DISCLOSURE OF THE INVENTION

[0003] This invention relates to new aminoalcohol derivatives which areβ₃ adrenergic receptor agonists and salts thereof.

[0004] More particularly, it relates to new aminoalcohol derivatives andsalts thereof which have gut sympathomimetic, anti-ulcerous,anti-pancreatitis, lipolytic, anti-urinary incontinence,anti-pollakiuria activities, anti-diabetes and anti-obesity, toprocesses for the preparation thereof, to a pharmaceutical compositioncomprising the same and to a method of using the same therapeutically inthe treatment and/or prevention of gastro-intestinal disorders caused bysmooth muscle contractions in a human being or an animal.

[0005] One object of this invention is to provide new and usefulaminoalcohol derivatives and salts thereof which have gutsympathomimetic, anti-ulcerous, lipolytic, anti-urinary incontinence,anti-pollakiuria activities, anti-diabetes and anti-obesity.

[0006] Another object of this invention is to provide processes for thepreparation of said aminoalcohol derivatives and salts thereof.

[0007] A further object of this invention is to provide a pharmaceuticalcomposition comprising, as an active ingredient, said aminoacoholderivatives and salts thereof.

[0008] Still further object of this invention is to provide atherapeutical method for the treatment and/or prevention of aforesaiddiseases in a human being or an animal, using said aminoalcoholderivatives and salts thereof.

[0009] The object aminoalcohol derivatives of this invention are new andcan be represented by compound of the following formula [I]:

[0010] wherein

[0011] (in which R⁷ is hydrogen or lower alkyl),

[0012] Y is bond, —O—(CH₂)_(n)— (in which n is 1, 2, 3 or 4),—(CH₂)_(m)— (in which m is 1, 2, 3 or 4),

[0013] Z is cyano, tetrazolyl, (benzylsulfonyl)carbamoyl,benzoylsulfamoyl, formyl, carboxy or protected carboxy,

[0014] R¹ is hydrogen, lower alkyl or halogen,

[0015] R² is hydrogen or an amino protective group,

[0016] R³ is hydrogen or lower alkyl,

[0017] R⁴ is hydrogen or lower alkyl,

[0018] R⁵ and R⁸ are each independently hydrogen, halogen, hydroxy,lower alkyl, lower alkenyl, lower alkoxy, hydroxy(lower)alkoxy, mono(ordi or tri)halo(lower)alkoxy, lower alkoxy(lower)alkoxy, loweralkenyloxy, cyclo(lower)alkyloxy, cyclo(lower)alkyl(lower)alkoxy,benzyloxy, phenoxy, lower alkylthio, cyclo(lower)alkylthio, loweralkylsulfonyl, cyclo(lower)alkylsulfonyl, amino, mono(ordi)(lower)alkylamino, mono(or di or tri)halo(lower)alkyl, cyano,piperidinyl or phenyl,

[0019] R⁶ is hydrogen, lower alkyl or halogen,

[0020] R⁹ is hydrogen or lower alkyl, and

[0021] i is 1 or 2,

[0022] provided that

[0023] (1) when X is bond,

[0024]  then R⁵ is not hydrogen, or

[0025] (2) when i is 1,

[0026] or a salt thereof.

[0027] According to this invention, the object compounds can be preparedby processes which are illustrated in the following schemes.

[0028] wherein

[0029] X, Y, Z, R¹, R², R³, R⁴, R⁵, R⁶, R⁸, R⁹ and i are each as definedabove,

[0030] R_(a) ² is an amino protective group,

[0031] R¹⁰ is lower alkyl, and

[0032] X₁ and X₂ are each a leaving group.

[0033] As to the starting compounds [II], [III], [Ia], [IV], [V], [VI]and [VII], some of them are novel and can be prepared by the proceduresdescribed in the Preparations and Examples mentioned below or aconventional manner.

[0034] In the above and subsequent description of the presentspecification, suitable examples of the various definition to beincluded within the scope of the invention are explained in detail inthe following.

[0035] The term “lower” is intended to mean a group having 1 to 6,preferably 1 to 4, carbon atom(s), unless otherwise indicated.

[0036] Suitable “lower alkyl” and “lower alkyl” moiety in the terms of“mono(or di)(lower)alkylamino” and “mono(or di or tri)halo(lower)alkyl”may include straight or branched one having 1 to 6 carbon atom(s), suchas methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, 1-methylpentyl, tert-pentyl, neo-pentyl, hexyl,isohexyl and the like.

[0037] Suitable “lower alkoxy” may include methoxy, ethoxy, propoxy,isopropoxy, butoxy, iso-butoxy, tert-butoxy, pentyloxy, tert-pentyloxy,hexyloxy and the like, in which preferable one is methoxy or ethoxy.

[0038] Suitable “cyclo(lower)alkyl” moiety in the term of“cyclo(lower)alkyloxy” may include cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl and the like, in which preferable one is cyclohexyl.

[0039] Suitable “halogen” may be fluoro, chloro, bromo and iodo, inwhich preferable one is chloro.

[0040] Suitable “mono(or di or tri)halo(lower)alkyl” may includechloromethyl, dichloromethyl, trichloromethyl, bromomethyl,dibromomethyl, tribromomethyl, fluoromethyl, difluoromethyl,trifluoromethyl, 1 or 2-chloroethyl, 1 or 2-bromoethyl, 1 or2-fluoroethyl, 1,1-difluoroethyl, 2,2-difluoroethyl and the like.

[0041] Suitable “protected carboxy” may include esterified carboxy suchas lower alkoxycarbonyl [e.g. methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl,hexyloxycarbonyl, etc.],

[0042] halo(lower)alkoxycarbonyl [e.g. (chloromethoxy)carbonyl,(2,2,2-trichloroethoxy)carbonyl, (2,2,2-trifluoroethoxy)-carbonyl,(2-chloropropoxy)carbonyl, (1-fluoro-4-bromobutoxy)carbonyl,(4-chloropentyloxy)carbonyl, (6-chlorohexyloxy)carbonyl, etc.],

[0043] higher alkoxycarbonyl [e.g. heptyloxycarbonyl, octyloxycarbonyl,2-ethylhexyloxycarbonyl, nonyloxycarbonyl, decyloxycarbonyl,3,7-dimethyloctyloxycarbonyl, undecyloxycarbonyl, dodecyloxycarbonyl,tridecyloxycarbonyl, tetradecyloxycarbonyl, pentadecyloxycarbonyl,3-methyl-10-ethyldodecyloxycarbonyl, hexadecyloxycarbonyl,heptadecyloxycarbonyl, octadecyloxycarbonyl, nonadecyloxycarbonyl,icosyloxycarbonyl, etc.],

[0044] aryloxycarbonyl [e.g. phenoxycarbonyl, naphthyloxycarbonyl,etc.],

[0045] aryl(lower)alkoxycarbonyl which may have one or more (preferably1 to 3) suitable substituent(s) such as phenyl(lower)alkoxycarbonylwhich may have nitro or lower alkoxy [e.g. benzyloxycarbonyl,phenethyloxycarbonyl, p-nitrobenzyloxycarbonyl,p-methoxybenzyloxycarbonyl, etc.], and the like,

[0046] in which preferable one is lower alkoxycarbonyl and morepreferable one is methoxycarbonyl, ethoxycarbonyl ortert-butoxycarbonyl.

[0047] Suitable “leaving group” may include hydroxy, reactive groupderived from hydroxy and the like.

[0048] Suitable “reactive group derived from hydroxy” may include acidresidue and the like.

[0049] Suitable “acid residue” may include halogen (e.g. fluoro, chloro,bromo, iodo), acyloxy (e.g. acetoxy, tosyloxy, mesyloxy,trifluoromethanesulfonyloxy, etc.) and the like.

[0050] Suitable example of “amino protective group” moiety may be commonamino protective group such as substituted or unsubstituted loweralkanoyl [e.g. formyl, acetyl, propionyl, trifluoroacetyl, etc.],phthaloyl, lower alkoxycarbonyl [e.g. tert-butoxycarbonyl,tert-amyloxycarbonyl, etc.], substituted or unsubstitutedaralkyloxycarbonyl [e.g. benzyloxycarbonyl, p-nitrobenzyloxycarbonyl,etc.], substituted or unsubstituted arenesulfonyl [e.g. benzenesulfonyl,tosyl, etc.], nitrophenylsulfenyl, ar(lower)alkyl [e.g. trityl, benzyl,etc.], and the like, in which preferable one is tert-butoxycarbonyl.

[0051] Suitable salts of the object aminoalcohol derivative [I] arepharmaceutically acceptable salts and include conventional non-toxicsalts such as an inorganic acid addition salt [e.g. hydrochloride,hydrobromide, sulfate, phosphate, etc.], an organic acid addition salt[e.g. formate, acetate, trifluoroacetate, oxalate, maleate, fumarate,tartrate, citrate, methanesulfonate, benzenesulfonate, toluenesulfonate,etc., an alkali metal salt [e.g. sodium salt, potassium salt, etc.] orthe like.

[0052] The Processes 1 to 6 for preparing the object compounds of thepresent invention are explained in detail in the following.

[0053] Process 1

[0054] The object compound [I] or a salt thereof can be prepared byreacting a compound [II] with a compound [III] or a salt thereof.

[0055] Suitable salt of the compound [III] may be the same as thoseexemplified for the compound [I].

[0056] The reaction is preferably carried out in the presence of a basesuch as an alkali metal carbonate [e.g. sodium carbonate, potassiumcarbonate, etc.], an alkaline earth metal carbonate [e.g. magnesiumcarbonate, calcium carbonate, etc.], an alkali metal bicarbonate [e.g.sodium bicarbonate, potassium bicarbonate, etc.], tri(lower)alkylamine[e.g. trimethylamine, triethylamine, etc.], picoline or the like.

[0057] The reaction is usually carried out in a conventional solvent,such as an alcohol [e.g. methanol, ethanol, propanol, isopropanol,etc.], diethyl ether, tetrahydrofuran, dioxane, or any other organicsolvent which does not adversely influence the reaction.

[0058] The reaction temperature is not critical, and the reaction can becarried out under cooling to heating.

[0059] Process 2

[0060] The object compound [Ib] or a salt thereof can be prepared bysubjecting a compound [Ia] or a salt thereof to elimination reaction ofthe amino protective group.

[0061] Suitable salts of the compounds [Ia] and [Ib] may be the same asthose exemplified for the compound [I].

[0062] This reaction can be carried out in a similar manner to that ofExample 11 mentioned below.

[0063] Process 3

[0064] The object compound [Ic] or a salt thereof can be prepared byreacting a compound [IV] or a salt thereof with a compound [V] or a saltthereof.

[0065] Suitable salts of the compounds [Ic], [IV] and [V] may be thesame as those exemplified for the compound [I].

[0066] This reaction can be carried out in a similar manner to that ofExample 15 mentioned below.

[0067] Process 4

[0068] The object compound [Ic] or a salt thereof can be, prepared byreacting a compound [IV] or a salt thereof with a compound [VI] or asalt thereof.

[0069] Suitable salts of the compound [Ic], [IV] and [VI] may be thesame as those exemplified for the compound [I].

[0070] This reaction can be carried out in a similar manner to that ofExample 9 mentioned below.

[0071] Process 5

[0072] The object compound [Id] or a salt thereof can be prepared byreacting a compound [VII] or a salt thereof with a compound [V] or asalt thereof.

[0073] Suitable salts of the compounds [Id], [VII] and [V] may be thesame as those exemplified for the compound [I].

[0074] This reaction can be carried out in a similar manner to that ofExample 7 mentioned below.

[0075] Process 6

[0076] The object compound [Ig] or a salt thereof can be prepared bysubjecting a compound [Ie] or a salt thereof to deesterificationreaction followed by subjecting a compound [If] or a salt thereof toelimination reaction of the amino protective group.

[0077] Suitable salts of the compound [Ig], [Ie] and [If] may be thesame as those exemplified for the compound [I].

[0078] These reactions can be carried out in a similar manner to that ofExample 18 mentioned below.

[0079] The compounds obtained by the above processes can be isolated andpurified by a conventional method such as pulverization,recrystallization, column chromatography, reprecipitation, or the like,and converted to the desired salt in conventional manners, if necessary.

[0080] It is to be noted that the compound [I] and the other compoundsmay include one or more stereoisomers due to asymmetric carbon atoms,and all of such isomers and mixture thereof are included within thescope of this invention.

[0081] It is further to be noted that isomerization or rearrangement ofthe object compound [I] may occur due to the effect of the light, acidbase or the like, and the compound obtained as the result of saidisomerization or rearrangement if also included within the scope of thepresent invention.

[0082] It is also to be noted that the solvating form of the compound[I] (e.g. hydrate, etc.) and any form of the crystal of the compound [I]are included within the scope of the present invention.

[0083] The object compound [I] or a salt thereof possesses gutsympathomimetic, anti-ulcerous, anti-pancreatitis, lipolytic,anti-urinary incontinence and anti-pollakiuria activities, and areuseful for the treatment and/or prevention of gastro-intestinaldisorders caused by smooth muscle contractions in human beings oranimals, and more parcitularly for the treatment and/or prevention ofspasm or hyperanakinesia in case of irritable bowel syndrome, gastritis,gastric ulcer, duodenal ulcer, enteritis, cholecystopathy, cholantitis,urinary calculus and the like; for the treatment and/or prevention ofulcer such as gastric ulcer, duodenal ulcer, peptic ulcer, ulcer causesby non steroidal anti-inflammatory drags, or the like; for the treatmentand/or prevention of dysuria or overactive bladder disorder such aspollakiuria, urinary incontinence, urge incontinence or the like in caseof nervous pollakiuria, neurogenic bladder dysfunction, nocturia,unstable bladder, cystospasm, chronic cystitis, chronic prostatitis,prostatic hypertrophy or the like; for the treatment and/or preventionof pancreatitis, obesity, diabetes, glycosuria, hyperlipidemia,hypertension, atherosclerosis, glaucoma, melancholia, depression or thelike; for the treatment and/or prevention of diseases as the result ofinsulin resistance (e.g. hypertension, hyperinsulinemia, etc.); for thetreatment and/or prevention of neurogenetic inflammation; and forreducing a wasting condition, and the like.

[0084] Additionally, β₃ adrenergic receptor agonists are known to lowertriglyceride and cholesterol levels and to raise high densitylipoprotein levels in mammals (U.S. Pat. No. 5,451,677). Accordingly,the object compound [I] in useful in the treatment and/or prevention ofconditions such as hyper-triglyceridaemia, hypercholesterolaemia and inlowering high density lipoprotein levels as well as in the treatment ofatherosclerotic and cardiovascular diseases and relates conditions.

[0085] Moreover, the object compound [I] is useful for inhibitinguterine contractions, preventing premature labor, and treating andpreventing dysmenorrhea.

[0086] In order to show the usefulness of the compound [I] for theprophylactic and therapeutic treatment of above-mentioned disease inhuman being or animals, a representative compound of the compound [I]was tested on the following pharmaceutical test.

[0087] Test

[0088] Effect on the increase in intravesical pressure induced bycarbachol in anesthetized dog

[0089] Test Compound

[0090] (1)4′-[(2R)-2-[[(2R)-2-Phenyl-2-hydroxyethyl]amino]-propyl]-3-methoxy-1,1′-biphenyl-4-carboxylicacid hydrochloride,

[0091] (2)4′-[2-[[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino]-ethyl]-2,3-dimethyl-1,1′-biphenyl-4-carboxylicacid hydrochloride,

[0092] (3)4′-[2-[[(2R)-2-Hydroxy-2-(3-pyridyl)ethyl]amino]ethyl]-2-methyl-1,1′-biphenyl-4-carboxylicacid dihydrochloride,

[0093] (4)4′-[(2R)-2-[[(2R)-2-Hydroxy-2-(3-pyridyl)ethyl]amino]-propyl]-3-methoxy-1,1′-biphenyl-4-carboxylicacid dihydrochloride.

[0094] Test Method

[0095] Female Beagle dogs weighing 8.0-15.0 kg were fasted for 24 hoursand maintained under halothane anesthesia. A 12F Foley catheter waslubricated with water soluble jelly, inserted into the urethral orificeand advanced approximately 10 cm until the balloon tip was placed wellinside the bladder. The balloon was then inflated with 5 ml of room airand catheter slowly withdrawn just part the first resistance that isfelt at the bladder neck. Urine was completely drained out through thecatheter, and 30 ml of biological saline was infused. The catheter wasconnected to pressure transducer, and intravesical pressure (IVP) wascontinuously recorded. The test compound was administered intravenouslyat 30 minutes before the administration of carbachol (1.8 μg/kg).Percent inhibition of IVP increase by test compound was calculated bydividing IVPa (IVP increase induced by carbachol after test compoundadministration) by IVPb (IVP increase induced by carbachol just beforetest compound administration). Test Results Treatment Percent inhibitionof IVP increase Test Compound (1) 93 (0.032 mg/kg) Test Compound (2) 91(0.032 mg/kg) Test Compound (3) 86 (0.032 mg/kg) Test Compound (4) 96(0.032 mg/kg)

[0096] Preferred embodiments of the object compound [I] are as follows:

[0097] X is bond, —O—, —OCH₂—, —S— or

[0098]  (in which R⁷ is hydrogen or lower alkyl (more preferably C₁-C₄alkyl, most preferably methyl)),

[0099] Y is bond, —O—(CH₂)_(n)— (in which n is 1, 2, 3 or 4),—(CH₂)_(m)— (in which m is 1, 2, 3 or 4),

[0100] Z is carboxy or lower alkoxycarbonyl (more preferably C₁-C₄alkoxycarbonyl, most preferably methoxycarbonyl, ethoxycarbonyl ortert-butoxycarbonyl),

[0101] R¹ is hydrogen or halogen (more preferably chloro),

[0102] R² is hydrogen,

[0103] R³ is hydrogen or lower alkyl (more preferably C₁-C₄ alkyl, mostpreferably methyl),

[0104] R⁴ is hydrogen,

[0105] R⁵ is halogen (more preferably chloro), hydroxy, lower alkyl(more preferably C₁-C₆, most preferably methyl), lower alkoxy (morepreferably C₁-C₆ alkoxy, most preferably methoxy, ethoxy, propoxy,isopropoxy, butoxy or pentyloxy), hydroxy(lower)alkoxy (more preferablyhydroxy(C₁-C₄)alkyl, most preferably 2-hydroxyethoxy), mono(or di ortri)halo(lower)alkoxy (more preferably mono(or di ortri)halo(C₁-C₄)alkoxy, most preferably 2-fluoroethoxy,2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, 3-fluoropropoxy or3,3,3-trifluoropropoxy), lower alkoxy(lower)alkoxy (more preferablyC₁-C₄ alkoxy(C₁-C₄)alkoxy, most preferably 2-methoxyethoxy), loweralkenyloxy (more preferably C₂-C₄ alkenyl, most preferably allyloxy),cyclo(lower)alkyloxy (more preferably cyclo(C₃-C₆)alkyloxy, mostpreferably cyclohexyloxy), phenoxy or phenyl,

[0106] R⁶ is hydrogen,

[0107] R⁸ is hydrgen or lower alkyl (more preferably C₁-C₄ alkyl, mostpreferably methyl),

[0108] R⁹ is hydrogen or lower alkyl (more preferably C₁-C₄ alkyl, mostpreferably methyl), and

[0109] i is 1 or 2.

[0110] More preferred embodiments of the object compound [I] are asfollows:

[0111] X is bond, —O—, —OCH₂—, —S— or

[0112]  (in which R⁷ is hydrogen or lower alkyl (more preferably C₁-C₄alkyl, most preferably methyl)),

[0113] Y is bond, —O—(CH₂)_(n)— (in which n is 1 or 2) or —(CH₂)_(m)—(in which m is 1 or 2),

[0114] Z is carboxy or lower alkoxycarbonyl (more preferably C₁-C₄alkoxycarbonyl, most preferably methoxycarbonyl, ethoxycarbonyl ortert-butoxycarbonyl),

[0115] R¹ is hydrogen or halogen (more preferably chloro),

[0116] R² is hydrogen,

[0117] R³ is hydrogen or lower alkyl (more preferably C₁-C₄ alkyl, mostpreferably methyl),

[0118] R⁴ is hydrogen,

[0119] R⁵ is hydrogen, halogen (more preferably chloro), hydroxy, loweralkyl (more preferably C₁-C₆, most preferably methyl), or lower alkoxy(more preferaly C₁-C₆ alkoxy, most preferably methoxy),

[0120] R⁶ is hydrogen,

[0121] R⁸ is hydrogen or lower alkyl (more preferably C₁-C₄ alkyl, mostpreferably methyl), and

[0122] i is 1.

[0123] Further more preferred embodiments of the compound [I] are asfollows:

[0124] X is bond,

[0125] Y is bond,

[0126] Z is carboxy or lower alkoxycarbonyl (more preferably C₁-C₄alkoxycarbonyl, most preferably methoxycarbonyl, ethoxycarbonyl ortert-butoxycarbonyl),

[0127] R¹ is hydrogen or halogen (more preferably chloro),

[0128] R² is hydrogen,

[0129] R³ is hydrogen or lower alkyl (more preferably C₁-C₄ alkyl, mostpreferably methyl),

[0130] R⁴ is hydrogen,

[0131] R⁵ is hydrogen (more preferably chloro), hydroxy, lower alkyl(more preferably C₁-C₄ alkyl, most preferably methyl) or lower alkoxy(more preferably C₁-C₄ alkoxy, most preferably methoxy or ethoxy),

[0132] R⁶ is hydrogen,

[0133] R⁸ is hydrogen or lower alkyl (more preferably C₁-C₄ alkyl, mostpreferably methyl),

[0134] R⁹ is hydrogen or lower alkyl (more preferably C₁-C₄ alkyl, mostpreferably methyl), and

[0135] i is 1.

[0136] The following Preparations and Examples are given for the purposeof illustrating this invention.

[0137] Preparation 1

[0138] A solution of N-benzyl-2-(4-bromophenyl)ethanamine (13.5 g) inethanol (270 ml) was added (2R)-2-(3-chlorophenyl)oxirane (8.63 g) andthe solution was refluxed for 48 hours. After cooling to roomtemperature, the solvent was removed by evaporation and the residue waschromatographed on silica gel (eluent: hexane/ethyl acetate=9/1) to give(1R)-2-[benzyl[2-(4-bromophenyl)ethyl]amino]-1-(3-chlorophenyl)ethanol(18.6 g) as a colorless oil.

[0139] NMR (CDCl₃, δ): 2.58 (1H, dd, J=10, 13 Hz), 2.68-2.89 (5H, m),3.56 (1H, d, J=13 Hz), 3.92 (1H, d, J=13 Hz), 4.59 (1H, dd, J=3.4, 10Hz), 6.97 (2H, d, J=8.3 Hz), 7.21-7.40 (12H, m)

[0140] (+)ESI-MS (m/z): 444 and 446 (MH⁺)

[0141] Preparation 2

[0142] To a solution of(1R)-2-[benzyl[2-(4-bromophenyl)ethyl]amino]-1-(3-chlorophenyl)ethanol(18.5 g) in N,N-dimethylformamide (40 ml) were successively addedimidazole (3.96 g) and tert-butyldimethylsilyl chloride (7.52 g) and thesolution was stirred at room temperature for 14 hours. The reactionmixture was quenched by the addition of water (100 ml) and extractedwith ethyl acetate (100 ml×1). The extract was washed with water (100ml×2), brine (100 ml×1), and dried over magnesium sulfate. Filtrationfollowed by evaporation gave a colorless oil, which was chromatographedon silica gel (eluent:hexane/ethyl acetate) to give(2R)-N-benzyl-N-[2-(4-bromophenyl)ethyl]-2-[[tert-butyl(dimethyl)silyl]oxy]-2-(3-chlorophenyl)ethanamine(21.0 g) as a colorless oil.

[0143] NMR (CDCl₃, δ): 0.15 (6H, s), 1.01 (9H, s), 2.72-2.82 (5H, m),2.92 (1H, dd, J=5.9, 13 Hz), 3.75 (1H, d, J=13.7 Hz), 3.86 (1H, d,J=13.7 Hz), 4.71 (1H, t-like, J=6.2 Hz), 7.01 (2H, d, J=8.3 Hz),7.26-7.47 (9H, m), 7.48 (2H, d, J=8.3 Hz)

[0144] (+)ESI-MS (m/z): 558 and 560 (MH⁺)

[0145] Preparation 3

[0146] To a solution of tert-butyl[2-(4-bromophenyl)ethyl][(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]carbamate(500 mg) in 1,2-dimethoxyethane (6 ml) was added5-formyl-2-thiopheneboronic acid (206 mg),tetrakis(triphenylphosphine)palladium (63 mg) and aqueous solution ofsodium carbonate (2M, 1.0 ml), and the mixture was stirred at 80° C. for7 hours under nitrogen. The mixture was diluted with ethyl acetate andwater. The organic layer was separated, washed with brine, dried overmagnesium sulfate and evaporated under reduced pressure. The residue waspurified by column chromatography on silica gel (hexane/ethylacetate=3/1) to give tert-butyl[(2R)-2-(3-chlorophenyl)-2-hydrxyethyl][2-[4-(5-formyl-2-thienyl)phenyl]ethyl]carbamate(187 mg).

[0147] (+)ESI-MS (m/z): 508 (M+Na)⁺

[0148] Preparation 4

[0149] To a suspension of tert-butyl[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl][2-(4-hydroxyphenyl)ethyl]carbamate(710 mg), 4-[[tert-butyl(dimethyl)silyl]oxy]phenylboronic acid (457 mg),triethylamine (1.26 ml) and powdered 4 Å molecular sieves (700 mg) indichloromethane (18 ml) was added copper(II) acetate (330 mg), and themixture was stirred at room temperature for 18 hours under ambientatmosphere. The resulting slurry was filtered off, and the filtrate wasevaporated under reduced pressure. The residue was purified by columnchromatography on silica gel (hexane/ethyl acetate=2/1) to givetert-butyl[2-[4-[4-[[tert-butyl(dimethyl)silyl]oxy]phenoxy]phenyl]ethyl][(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]carbamate(600 mg).

[0150] (−)ESI-MS (m/z): 569 (M−H)⁻

[0151] Preparation 5

[0152] The following compounds were obtained according to a similarmanner to that of Preparation 4.

[0153] (1) tert-Butyl[2-[4-[[4-[[tert-butyl(dimethyl)silyl]oxy]-phenyl]amino]phenyl]ethyl][(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]carbamate

[0154] (+)ESI-MS (m/z): 597 (M+H)⁺

[0155] (2) tert-Butyl[2-[4-[[4-[[tert-butyl(dimethyl)silyl]oxy]-phenyl](methyl)amino]phenyl]ethyl][(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]carbamate

[0156] (+)ESI-MS (m/z): 611 (M+H)⁺

[0157] Preparation 6

[0158] To a solution of tert-butyl[2-(4-aminophenyl)ethyl][(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]carbamate(1.75 g) and formaldehyde (37% w/w solution in water, 390 μl) in1,2-dichloroethane (20 ml) was added sodium triacetoxyborohydride (1.23g), and the mixture was stirred at room temperature for 18 hours undernitrogen atmosphere. The resulting mixture was poured into a mixture of1N sodium hydroxide and chloroform, and the mixture was stirred for 20minutes. The organic layer was separated, washed with brine, dried overmagnesium sulfate and evaporated under reduced pressure. The residue waspurified by column chromatography on silica gel (hexane/ethylacetate=2/1) to give tert-butyl[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl][2-[4-(methylamino)phenyl]ethyl]carbamate(550 mg).

[0159] (+)ESI-MS (m/z): 405 (M+H)⁺

[0160] Preparation 7

[0161] To a suspension of 2-[4-[(4-methoxyphenyl)thio]phenyl]-ethanamine(6.3 g) in methanol (45 ml) and tetrahydrofuran (10 ml) was added ethyltrifluoroacetate (2.89 ml), and the mixture was stirred at roomtemperature for 1 hour. The mixture was evaporated under reducedpressure. The residue was purified by column chromatography on silicagel (hexane/ethyl acetate=2/1) to give2,2,2-trifluoro-N-[2-[4-[(4-methoxyphenyl)thio]phenyl]ethyl]acetamide(3.95 g).

[0162] (+)ESI-MS (m/z): 378 (M+Na)⁺

[0163] Preparation 8

[0164] Under nitrogen at 4° C., to a solution of2,2,2-trifluoro-N-[2-[4-[(4-methoxyphenyl)thio]phenyl]ethyl]-acetamide(1.5 g) in dichloromethane (15 ml) was added 1M boron tribromide indichloromethane (10.5 ml), and the mixture was stirred at roomtemperature for 15 hours. The mixture was evaporated under reducedpressure. The residue was dissolved in a mixture of dichloromethane andsaturated aqueous sodium bicarbonate. After separation, the organiclayer was dried over magnesium sulfate and evaporated under reducedpressure to give2,2,2-trifluoro-N-[2-[4-[(4-hydroxyphenyl)thio]phenyl]ethyl]acetamide(1.42 g).

[0165] (+)ESI-MS (m/z): 364 (M+Na)⁺

[0166] Preparation 9

[0167] To a solution of2,2,2-trifluoro-N-[2-[4-[(4-hydroxyphenyl)thio]phenyl]ethyl]acetamide(480 mg) in methanol (5.0 ml) was added 1N sodium hydroxide solution(2.8 ml). The mixture was refluxed for 12 hours. The mixture wasevaporated under reduced pressure. The residue was dissolved in amixture of dichloromethane (40 ml), 1N hydrochloric acid solution (2.0ml) and water (15 ml). After separation, the organic layer was driedover magnesium sulfate and evaporated under reduced pressure to give4-[[4-(2-aminoethyl)phenyl]thio]phenol (300 mg).

[0168] (−)ESI-MS (m/z): 244 (M−H)⁻

[0169] Preparation 10

[0170] 4-[[4-(2-Aminoethyl)phenyl]thio]phenol (295 mg) and(2R)-2-(3-chlorophenyl)oxirane (186 mg) in ethanol (3.5 ml) was refluxedfor 6 hours. The mixture was evaporated. The residue was purified bycolumn chromatography on silica gel (chloroform/methanol=100/3) to give4-[[4-[2-[[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]phenyl]thio]phenol(155 mg).

[0171] (+)ESI-MS (m/z): 400 (M+H)⁺

[0172] The object compound above was protected at the imino group in aconventional manner to give tert-butyl[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl][2-[4-[(4-hydroxyphenyl)thio]phenyl]ethyl]carbamate(200 mg).

[0173] (+)ESI-MS (m/z): 500 (M+H)⁺

[0174] Preparation 11

[0175] The following compounds were obtained according to a similarmanner to that of Preparation 10.

[0176] (1)(1R)-2-[[2-(4-Bromophenyl)ethyl]amino]-1-(3-chlorophenyl)ethanol

[0177] (+)ESI-MS (m/z): 354 (M+H)⁺

[0178] (2) tert-Butyl[2-(4-bromophenyl)ethyl][(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]carbamate

[0179] (+)ESI-MS (m/z): 454 (M+H)⁺

EXAMPLE 1

[0180] To a solution of tert-butyl[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl](2-[4-(5-formyl-2-thienyl)phenyl]ethyl]-carbamate(180 mg) in acetonitrile (2 ml) and pH 4 buffer solution (sodiumdihydrogenphosphate) (1 ml) was added 30% hydrogen peroxide solution (30μl) and 80% sodium chlorite (67 mg) below 10° C. The reaction mixturewas stirred at 50° C. for 3 hours. The mixture was diluted with ethylacetate, washed with water and brine, dried over magnesium sulfate andevaporated under reduced pressure to give5-[4-[2-[(tert-butoxycarbonyl)[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]phenyl]-2-thiophenecarboxylicacid (160 mg).

[0181] (−)ESI-MS (m/z): 500 (M−H)⁻

EXAMPLE 2

[0182] The following compounds were obtained according to a similarmanner to that of Example 4.

[0183] (1)5-[4-[2-[[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]-amino]ethyl]phenyl]-2-thiophenecarboxylicAcid Hydrochloride

[0184] NMR (DMSO-d₆, δ): 3.00-3.25 (6H, m), 4.95-4.99 (1H, m), 6.34 (1H,br), 7.33-7.47 (6H, m), 7.55 (1H, d, J=3.9 Hz), 7.70-7.81 (3H, m), 9.05(1H, br)

[0185] (−)ESI-MS (m/z): 400 (M−HCl−H)⁻

[0186] (2)[4-[[4-[2-[[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]-amino]ethyl]phenyl]amino]phenoxy]aceticAcid Hydrochloride

[0187] NMR (DMSO-d₆, δ): 2.84-3.30 (6H, m), 4.39 (1H, br), 4.59 (2H, s),4.97-5.03 (1H, m), 6.37 (1H, br), 6.80-7.07 (8H, m), 7.34-7.48 (4H, m),8.85 (1H, br), 9.11 (1H, br)

[0188] (−)ESI-MS (m/z): 439 (M−HCl−H)⁻

[0189] (3)[4-[[4-[2-[[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]-amino]ethyl]phenyl](methyl)amino]phenoxy]aceticAcid Hydrochloride

[0190] NMR (DMSO-d₆, δ): 2.85-3.23 (6H, m), 3.17 (3H, s), 3.89-4.15 (1H,br), 4.65 (2H, s), 4.98-5.02 (1H, m), 6.68-7.08 (8H, m), 7.34-7.46 (4H,m), 8.86 (1H, br), 9.14 (1H, br)

[0191] (−)ESI-MS (m/z): 453 (M−HCl−H)⁻

[0192] (4)[4-[[4-[2-[[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]-amino]ethyl]phenyl]thio]phenoxy]aceticAcid Hydrochloride

[0193] NMR (DMSO-d₆, δ): 2.94-3.33 (6H, m), 4.70 (2H, s), 4.97-5.01 (1H,m), 6.34 (1H, br), 6.96 (2H, d, J=8.7 Hz), 7.02-7.23 (4H, m), 7.33-7.45(6H, m), 8.97-9.18 (1H, br)

[0194] (−)ESI-MS (m/z): 456 (M−HCl−H)⁻

EXAMPLE 3

[0195] To a solution of tert-butyl[2-[4-[4-[[tert-butyl(dimethyl)silyl]oxy]phenoxy]phenyl]ethyl][(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]carbamate(370 mg) in tetrahydrofuran (4.0 ml) was added 1M tetrabutylammoniumfluoride in tetrahydrofuran (1.2 ml), and the mixture was stirred atroom temperature for 1 hour. The mixture was partitioned between ethylacetate and water. The organic layer was separated, washed with waterand brine, dried over magnesium sulfate and evaporated under reducedpressure to give a phenol product. To a solution of the product andpotassium carbonate (94 mg) in N,N-dimethylformamide (4.0 ml) was addedtert-butyl bromoacetate (133 mg), and the mixture was stirred at roomtemperature for 5 hours. The mixture was partitioned between ethylacetate and water. The organic layer was separated, washed with waterand brine, dried over magnesium sulfate and evaporated under reducedpressure. The residue was purified by column chromatography on silicagel (hexane/ethyl acetate=2/1) to give tert-butyl[4-[4-[2-[(tert-butoxycarbonyl)[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]phenoxy]phenoxy]-acetate(360 mg).

[0196] (−)ESI-MS (m/z): 597 (M−H)⁻

EXAMPLE 4

[0197] A solution of tert-butyl[4-[4-[2-[(tert-butoxycarbonyl)[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]-amino]ethyl]phenoxy]phenoxy]acetate(305 mg) and 4N hydrochloride in 1,4-dioxane (5.0 ml) was stirred atroom temperature for 24 hours. The resulting solid was collected byfiltration and dried to give[4-[4-[2-[[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]phenoxy]phenoxy]-aceticacid hydrochloride (220 mg) as a white solid.

[0198] NMR (DMSO-d₆, δ): 2.95-3.33 (6H, m), 4.65 (2H, s), 4.99-5.04 (1H,m), 6.35 (1H, br), 6.83-7.00 (6H, m), 7.23 (9H, d, J=8.5 Hz), 7.39-7.47(4H, m), 8.98-9.12 (1H, br)

[0199] (+)ESI-MS (m/z): 442 (M−HCl+H)⁺

EXAMPLE 5

[0200] To a suspension of tert-butyl[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl][2-(4-hydroxyphenyl)ethyl]carbamate(550 mg), (4-methoxycarbonylphenyl)boronic acid (300 mg), triethylamine(1.0 ml) and powdered 4 Å molecular sieves (600 mg) in dichloromethane(8 ml) was added copper(II) acetate (255 mg), and the mixture wasstirred at room temperature for 18 hours under ambient atmosphere. Theresulting slurry was filtered off, and the filtrate was evaporated underreduced pressure. The residue was purified by column chromatography onsilica gel (hexane/ethyl acetate=2/1) to give methyl4-[4-[2-[(tert-butoxycarbonyl)[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]phenoxy]benzoate(185 mg).

[0201] (+)ESI-MS (m/z): 526 (M+H)⁺

EXAMPLE 6

[0202] To a solution of methyl4-[4-[2-[(tert-butoxycarbonyl)[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]phenoxy]benzoate(183 mg) in ethanol (1.2 ml) was added 1N aqueous sodium hydroxidesolution (0.6 ml), and the mixture was stirred at 40° C. for 3 hours.The solvent was removed by evaporation, and the aqueous solution wasacidified with 1N aqueous hydrochloride solution and extracted withethyl acetate (30 ml×2). The combined organic layers were washed withwater and brine, dried over magnesium sulfate and evaporated underreduced pressure to give a benzoic acid product. To a solution of theproduct in tetrahydrofuran (2.0 ml) was added 4N hydrochloride in1,4-dioxane (1.0 ml), and the mixture was stirred at room temperaturefor 12 hours. The resulting solid was collected by filtration and driedto give4-[4-[2-[[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]-phenoxy]benzoicacid hydrochloride (127 mg).

[0203] NMR (DMSO-d₆, δ): 3.00-3.28 (6H, m), 4.99-5.04 (1H, m), 6.35 (1H,br), 6.97-7.12 (4H, m), 7.32-7.48 (6H, m), 7.90-7.98 (2H, m), 9.03-9.35(1H, br)

[0204] (−)ESI-MS (m/z): 410 (M−HCl−H)⁻

EXAMPLE 7

[0205] To a solution of tert-butyl[2-(4-bromophenyl)ethyl]-[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]carbamate(400 mg) in 1,2-dimethoxyethane (6 ml) was added(4-methoxycarbonyl-2-methylphenyl)boronic acid (171 mg),tetrakis(triphenylphosphine)palladium (55 mg) and aqueous solution ofsodium carbonate (2M, 0.92 ml), and the mixture was stirred at 80° C.for 2 hours under nitrogen. The mixture was diluted with ethyl acetateand water. The organic layer was separated, washed with brine, driedover magnesium sulfate and evaporated under reduced pressure. Theresidue was purified by column chromatography on silica gel(hexane/ethyl acetate=2/1) to give methyl4′-[2-[(tert-butoxycarbonyl)[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]-amino]ethyl]-2-methyl-1,1′-biphenyl-4-carboxylate(320 mg).

[0206] (+)ESI-MS (m/z): 524 (M+H)⁺

EXAMPLE 8

[0207] The following compounds were obtained according to a similarmanner to that of Example 6.

[0208] (1)5-Chloro-6-[4-[2-[[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]phenoxy]nicotinicAcid Hydrochloride

[0209] NMR (DMSO-d₆, δ): 3.04-3.32 (6H, m), 5.03-5.07 (1H, m), 5.14 (1H,br), 7.18 (2H, d, J=8.5 Hz), 7.33-7.48 (6H, m), 8.38 (1H, d, J=2.0 Hz),8.54 (1H, d, J=2.0 Hz), 9.00 (1H, br), 9.35 (1H, br)

[0210] (−)ESI-MS (m/z): 445 (M−HCl−H)⁻

[0211] (2)4′-[2-[[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino]-ethyl]-2-methyl-1,1′-biphenyl-4-carboxylicAcid Hydrochloride

[0212] NMR (DMSO-d₆, δ): 2.28 (1H, s), 3.01-3.27 (6H, m), 5.00-5.04 (1H,m), 6.36 (1H, br), 7.28-7.48 (9H, m), 7.79-7.90 (2H, m), 9.02 (1H, br)

[0213] (−)ESI-MS (m/z): 408 (M−HCl−H)⁻

EXAMPLE 9

[0214] To a solution of tert-butyl[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl][2-(4-hydroxyphenyl)ethyl]carbamate(600 mg) and potassium carbonate (254 mg) in dimethylsulfoxide (6.0 ml)was added methyl 5,6-dichloro-3-pyridinecarboxylate (347 mg), and themixture was stirred at room temperature for 12 hours. The mixture waspartitioned between ethyl acetate and water. The organic layer wasseparated, washed with water and brine, dried over magnesium sulfate andevaporated under reduced pressure. The residue was purified by columnchromatography on silica gel (hexane/ethyl acetate=2/1) to give methyl6-[4-[2-[(tert-butoxycarbonyl)[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]phenoxy]-5-chloronicotinate(770 mg).

[0215] (+)ESI-MS (m/z): 561 (M+H)⁺

EXAMPLE 10

[0216] Under nitrogen at 5° C., to a solution of tert-butyl[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl][2-(4-hydroxyphenyl)ethyl]carbamate(1.5 g), ethyl [3-(hydroxymethyl)phenoxy]acetate (885 mg) and triphenylphosphine (1.1 g) in tetrahydrofuran (30 ml) was added diethylazodicarboxylate (0.66 ml). The mixture was stirred at room temperaturefor 12 hours and evaporated under reduced pressure. The residue waspurified by column chromatography on silica gel (hexane/ethylacetate=2/1) to give ethyl[3-[[4-[2-[(tert-butoxycarbonyl)[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]phenoxy]methyl]-phenoxy]acetate(1.04 g).

[0217] (+)ESI-MS (m/z): 585 (M+H)⁺

EXAMPLE 11

[0218] To a solution of ethyl[3-[[4-[2-[(tert-butoxycarbonyl)[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]-amino]ethyl]phenoxy]methyl]phenoxy]acetate(1.0 g) in tetrahydrofuran (5.0 ml) was added 4N hydrochloride indioxane (4.3 ml). The mixture was stirred at room temperature for 8hours and evaporated under reduced pressure. The residue was dilutedwith ethyl acetate and saturated sodium bicarbonate solution. Theorganic layer was separated, washed with brine, dried over magnesiumsulfate and evaporated under reduced pressure. The residue was purifiedby column chromatography on silica gel (methanol/chloroform=1/20) togive ethyl[3-[[4-[2-[[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]phenoxy]-methyl]phenoxy]acetate(632 mg).

[0219] (+)ESI-MS (m/z): 484 (M+H)⁺

[0220] The object compound above was hydrolyzed in a conventional mannerto give sodium[3-[[4-[2-[[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl-]phenoxy]methyl]-phenoxy]acetate(492 mg).

[0221] NMR (DMSO-d₆, δ): 2.56-2.73 (6H, m), 4.09 (2H, s), 4.58-4.64 (1H,m), 4.98 (2H, s), 6.72-6.77 (1H, m), 6.85-6.91 (4H, m), 7.08 (2H, d,J=8.5 Hz), 7.17-7.26 (4H, m), 7.38 (1H, s)

[0222] (−)ESI-MS (m/z): 454 (M−Na−H)⁻

EXAMPLE 12

[0223] The following compounds were obtained according to a similarmanner to that of Example 3.

[0224] (1) tert-Butyl[4-[[4-[2-[(tert-butoxycarbonyl)[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]phenyl]amino]-phenoxy]acetate

[0225] (+)ESI-MS (m/z): 597 (M+H)⁺

[0226] (2) tert-Butyl[4-[[4-[2-[(tert-butoxycarbonyl)[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]phenyl]-(methyl)amino]phenoxy]acetate

[0227] (+)ESI-MS (m/z): 611 (M+H)⁺

EXAMPLE 13

[0228] To a solution of tert-butyl[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl][2-[4-[(4-hydroxyphenyl)thio]phenyl]ethyl]-carbamate(195 mg) and potassium carbonate (59 mg) in N,N-dimethylformamide (3 ml)was added tert-butyl bromoacetate (84 mg), and the mixture was stirredat room temperature for 3 hours. The mixture was partitioned betweenethyl acetate and water. The organic layer was separated, washed withwater and brine, dried over magnesium sulfate and evaporated underreduced pressure. The residue was purified by column chromatography onsilica gel (hexane/ethyl acetate=3/1) to give tert-butyl[4-[[4-[2-[(tert-butoxycarbonyl)[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]phenyl]thio]-phenoxy]acetate(168 mg).

[0229] (+)ESI-MS (m/z): 636 (M+Na)⁺

[0230] Preparation 12

[0231] To a solution of 4-bromo-2-fluorobenzoate (1.5 g) inN,N-dimethylformamide (30 ml) was added bis(pinacolato)-diboron (1.8 g),1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloridedichloromethanecomplex (1:1) (263 mg) and potassium acetate (1.9 g), and the mixturewas stirred at 100° C. for 18 hours under nitrogen. The mixture wasdiluted with ethyl acetate and water. The organic layer was separated,washed with brine, dried over magnesium sulfate and evaporated. Theresidue was purified by column chromatography on silica gel(hexane/ethyl acetate=5/1) to give methyl2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (350mg).

[0232] (+)ESI-MS (m/z): 303 (M+Na)⁺

[0233] Preparation 13

[0234] To a solution of methyl 4-bromo-2-methoxybenzoate (2.0 g) in1,4-dioxane (40 ml) was added bis(pinacolato)diboron (2.07 g),dichlorobis(triphenylphosphine)palladium(II) (286 mg) and potassiumacetate (2.4 g), and the mixture was stirred at 95° C. for 10 hoursunder nitrogen. The mixture was diluted with ethyl acetate and water.The organic layer was separated, washed with brine, dried over magnesiumsulfate and evaporated. The residue was purified by columnchromatography on silica gel (hexane/ethyl acetate=3/1) to give methyl2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (2.0g).

[0235] (+)ESI-MS (m/z): 293 (M+H)⁺

[0236] Preparation 14

[0237] To a suspension of methyl2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (2.0g) in acetone (70 ml) and water (70 ml) was added ammonium acetate (1.11g) and sodium periodate (3.08 g), and the mixture was stirred at roomtemperature for 15 hours. The solvent was evaporated and the residue wasdiluted with ethyl acetate. The organic layer was separated, washed withwater and brine, dried over magnesium sulfate and evaporated underreduced pressure to give [3-methoxy-4-(methoxycarbonyl)phenyl]-boronicacid (1.4 g).

[0238] (+)ESI-MS (m/z): 209 (M−H)⁻

[0239] Preparation 15

[0240] The following compounds were obtained according to a similarmanner to that of Preparation 14.

[0241] (1) [3-Fluoro-4-(methoxycarbonyl)phenyl]boronic Acid

[0242] (+)ESI-MS (m/z): 197 (M−H)⁻

[0243] (2) [2-Chloro-4-(methoxycarbonyl)phenyl]boronic Acid

[0244] (+)ESI-MS (m/z): 213 (M−H)⁻

[0245] (3) [4-(Ethoxycarbonyl)-2-methoxyphenyl]boronic Acid

[0246] (+)ESI-MS (m/z): 223 (M−H)⁻

[0247] Preparation 16

[0248] To a solution of ethyl3-methoxy-4-[[(trifluoromethyl)sulfonyl]oxy]benzoate (1.52 g) in1,4-dioxane (35 ml) was added bis(pinacolato)diboron (1.18 g),1,1′-bis(diphenyl-phosphino)ferrocene-palladium(II)dichloridedichloromethanecomplex (1:1) (309 mg) and potassium acetate (1.36 g), and the mixturewas stirred at 100° C. for 10 hours under nitrogen. The mixture wasdiluted with ethyl acetate and water. The organic layer was separated,washed with brine, dried over magnesium sulfate and evaporated. Theresidue was purified by column chromatography on silica gel(hexane/ethyl acetate=5/1) to give ethyl3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (700mg).

[0249] (+)ESI-MS (m/z): 293 (M+H)⁺

[0250] Preparation 17

[0251] The following compound was obtained according to a similar mannerto that of Preparation 16.

[0252] Methyl3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate

[0253] (+)ESI-MS (m/z): 297 (M+H)⁺

[0254] Preparation 18

[0255] To a solution of tert-butyl[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl][2-(4-hydroxyphenyl)ethyl]carbamate(5.0 g) and 2,6-lutidine (2.97 ml) in dichloromethane (75 ml) was addedtrifluoromethanesulfonic anhydride (2.36 ml) dropwise at −70° C. undernitrogen and the mixture was stirred at −70° C. for 30 minutes. Themixture was allowed to warm to room temperature and evaporated underreduced pressure. The residue was partitioned between ethyl acetate andwater. The organic layer was separated, washed with saturated sodiumbiscarbonate solution and brine, dried over magnesium sulfate andevaporated under reduced pressure. The residue was purified by columnchromatography on silica gel (hexane/ethyl acetate=2/1) to give4-[2-[(tert-butoxycarbonyl)[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]-amino]ethyl]phenyltrifluoromethanesulfonate (6.6 g).

[0256] (+)ESI-MS (m/z): 546 (M+Na)⁺

[0257] Preparation 19

[0258] To a solution of methyl 4-bromo-2-methylbenzoate (6.9 g) in1,4-dioxane (150 ml) was added bis(pinacolato)diboron (8.03 g),dichlorobis(triphenylphosphine)palladium(II) (1.69 g) and potassiumacetate (8.87 g), and the mixture was stirred at 95° C. for 2 hoursunder nitrogen. The mixture was diluted with ethyl acetate and water.The organic layer was separated, washed with 1N hydrochloric acid andbrine, dried over magnesium sulfate and evaporated. To a suspension ofthe crude product (11 g) in acetone (200 ml) and water (200 ml) wasadded ammonium acetate (5.1 g) and sodium periodate (14.1 g), and themixture was stirred at room temperature for 6 hours. The solvent wasevaporated, and the mixture was diluted with ethyl acetate. The organiclayer was separated, washed with water and brine, dried over magnesiumsulfate and evaporated under reduced pressure. The resultant solid wastriturated with diisopropyl ether to give[3-methyl-4-(methoxycarbonyl)phenyl]boronic acid (2.65 g).

[0259] (+)ESI-MS (m/z): 193 (M−H)⁻

[0260] Preparation 20

[0261] To a solution of 4-hydroxy-2,3-dimethylbenzaldehyde (1.9 g) andpyridine (5.12 ml) in dichloromethane (40 ml) was addedtrifluoromethanesulfonic anhydride (2.34 ml) under nitrogen and themixture was stirred at room temperature for 30 minutes and evaporatedunder reduced pressure. The residue was partitioned between ethylacetate and water. The organic layer was separated, washed withsaturated sodium bicarbonate solution and brine, dried over magnesiumsulfate and evaporated under reduced pressure to give4-formyl-2,3-dimethylphenyl trifluoromethanesulfonate (2.7 g).

[0262] (+)ESI-MS (m/z): 281 (M−H)⁻

[0263] Preparation 21

[0264] To a solution of 4-formyl-2,3-dimethylphenyltrifluoromethanesulfonate (2.5 g) in 1,4-dioxane (50 ml) was addedbis(pinacolato)diboron (2.47 g),1,1′-bis(diphenyl-phosphino)ferrocene-palladium(II)dichloridedichloromethanecomplex (1:1) (1.09 g) and potassium acetate (2.61 g), and the mixturewas stirred at 90° C. for 5 hours under nitrogen. The mixture wasdiluted with ethyl acetate and water. The organic layer was separated,washed with 1N hydrochloric acid and brine, dried over magnesium sulfateand evaporated. To a suspension of the crude product in acetone (80 ml)and water (80 ml) was added ammonium acetate (1.4 g) and sodiumperiodate (3.95 g), and the mixture was stirred at room temperature for6 hours. The solvent was evaporated, and the mixture was diluted withethyl acetate. The organic layer was separated, washed with water andbrine, dried over magnesium sulfate and evaporated under reducedpressure. The residue was purified by column chromatography on silicagel (hexane/ethyl acetate=1/1) to give(4-formyl-2,3-dimethylphenyl)boronic acid (560 mg).

[0265] (+)ESI-MS (m/z): 177 (M−H)

[0266] Preparation 22

[0267] To a solution of N-benzyl-N-[2-(4-bromophenyl)ethyl]-carbamate(1.3 g) in 1,2-dimethoxyethane (20 ml) was added[4-(methoxycarbonyl)-2-methylphenyl]boronic acid (792 mg),tetrakis(triphenylphosphine)palladium (360 mg) and aqueous solution ofsodium carbonate (2M, 4.1 ml), and the mixture was stirred at 80° C. for2 hours under nitrogen. The mixture was diluted with ethyl acetate andwater. The organic layer was separated, washed with brine, dried overmagnesium sulfate and evaporated under reduced pressure. The residue waspurified by column chromatography on silica gel (hexane/ethylacetate=3/1) to give methyl4′-[2-[[(benzyloxy)carbonyl]amino]ethyl]-2-methyl-1,1′-biphenyl-4-carboxylate(660 mg).

[0268] (+)ESI-MS (m/z): 426 (M+Na)⁺

[0269] Preparation 23

[0270] To a solution of2,2,2-trifluoro-N-[3-(4-iodophenyl)propyl]acetamide (2.5 g) in1,2-dimethoxyethane (15 ml) was added [4-(methoxycarbonyl)phenyl]boronicacid (1.51 g), tetrakis(triphenylphosphine)palladium (809 mg) andaqueous solution of sodium carbonate (2M, 7 ml), and the mixture wasstirred at 75° C. for 10 hours under nitrogen. The mixture was dilutedwith ethyl acetate and water. The organic layer was separated, washedwith brine, dried over magnesium sulfate and evaporated. The residue waspurified by column chromatography on silica gel (hexane/ethylacetate=2/1) to give methyl4′-[3-[(trifluoroacetyl)amino]propyl]-1,1′-biphenyl-4-carboxylate (920mg).

[0271] MS (m/z): 366 (M+H)

[0272] Preparation 24

[0273] The following compound was obtained according to a similar mannerto that of Preparation 23.

[0274] Ethyl4′-[2-[[(benzyloxy)carbonyl]amino]ethyl]-2-methoxy-1,1′-biphenyl-4-carboxylate

[0275] MS (m/z): 434 (M+H)

[0276] Preparation 25

[0277] A mixture of methyl4′-[3-[(trifluoroacetyl)amino]-propyl]-1,1′-biphenyl-4-carboxylate (920mg), 4N hydrochloride in ethanol (2 ml) and ethanol (2 ml) was refluxedfor 18 hours. The mixture was evaporated in vacuo. The residue wasdiluted with ethyl acetate and saturated aqueous sodium bicarbonatesolution. The organic layer was separated, washed with brine, dried overmagnesium sulfate and evaporated. The residue was purified by columnchromatography on silica gel (chloroform:methanol=100:1) to give ethyl4′-(3-aminopropyl)-1,1′-biphenyl-4-carboxylate (200 mg) as a colorlessfoam.

[0278] MS (m/z): 284 (M+H)

[0279] Preparation 26

[0280] To a solution of ethyl(1R)-1-(6-chloro-3-pyridyl)-2-[[3-(4-iodophenyl)propyl]amino]ethanol(2.0 g) in tetrahydrofuran (3.5 ml) was added di-tert-butyl dicarbonate(53 mg), and the mixture was stirred at room temperature for 2 hours.The mixture was evaporated. The residue was purified by columnchromatography on silica gel (hexane/ethyl acetate=2/1) to givetert-butyl[(2R)-2-(6-chloro-3-pyridyl)-2-hydroxyethyl][3-(4-iodophenyl)propyl]-carbamate(2.62 g).

[0281] MS (m/z): 517 (M+H)

[0282] Preparation 27

[0283] To a solution of2,2,2-trifluoro-N-[(1R)-2-(4-iodophenyl)-1-methylethyl]acetamide indioxane (10 ml) was added 1N sodium hydroxide (12 ml) and the mixturewas stirred for 1 hour at room temperature. The mixture was diluted withethyl acetate and water. The organic layer was separated, washed withbrine, dried over magnesium sulfate and evaporated to give[(1R)-2-(4-iodophenyl)-1-methylethyl]amine (2.34 g) as a yellow oil.

[0284] MS (m/z): 262 (M+H)

[0285] Preparation 28

[0286] A solution of [(1R)-2-(4-iodophenyl)-1-methylethyl]-amine (1.0 g)and 2-chloro-5-[(2R)-2-oxiranyl]pyridine (298 mg) in ethanol (10 ml) wasrefluxed for 18 hours. The mixture was evaporated in vacuo. To theresidue was added di-tert-butyl dicarbonate (418 mg) and tetrahydrofuran(10 ml) and the mixture was stirred at room temperature for 2 hours andthen evaporated. The residue was purified by column chromatography onsilica gel (hexane/ethyl acetate=1/1) to give tert-butyl[(2R)-2-(6-chloro-3-pyridyl)-2-hydroxyethyl][(1R)-2-(4-iodophenyl)-1-methylethyl]carbamate(700 mg).

[0287] MS (m/z): 517 (M+H)

[0288] Preparation 29

[0289] The following compound was obtained according to a similar mannerto that of Preparation 28.

[0290] tert-Butyl[(2R)-2-(6-chloro-3-pyridyl)-2-hydroxyethyl][2-(4-hydroxyphenyl)ethyl]carbamate

[0291] MS (m/z): 393 (M+H)

[0292] Preparation 30

[0293] Under nitrogen at −60° C., to a solution of tert-butyl[2-(4-hydroxyphenyl)ethl][(2R)-2-hydroxy-2-(3-pyridyl)ethyl]carbamate(570 mg) and 2,6-lutidine (0.22 ml) in dichloromethane (10 ml) was addedtrifluoromethanesulfonic anhydride (0.28 ml), and the mixture wasstirred at the same temperature for 1 hour. The resulting mixture waspoured into aqueous ammonia and the aqueous mixture was extracted withethyl acetate. The organic layer was washed successively with 1Nhydrochloric acid, water, saturated aqueous sodium bicarbonate andbrine, dried over anhydrous magnesium sulfate and evaporated underreduced pressure. The residue was purified by column chromatography onsilica gel (hexane/ethyl acetate=1:1) to give4-[2-[(tert-butoxycarbonyl)[(2R)-2-hydroxy-2-(3-pyridyl)ethyl]amino]-ethyl]phenyltrifluoromethanesulfonate (640 mg) as a colorless foam.

[0294] MS (m/z): 491 (M+H)

[0295] Preparation 31

[0296] The following compound was obtained according to a similar mannerto that of Preparation 30.

[0297]4-[2-[(tert-Butoxycarbonyl)[(2R)-2-hydroxy-2-(3-chlorophenyl)ethyl]amino]propyl]phenyltrifluoromethanesulfonate

[0298] MS (m/z): 538 (M+H)

[0299] Preparation 32

[0300] To a solution of2,2,2-trifluoro-N-[(1R)-1-methyl-2-phenylethyl]acetamide (3.75 g) inacetic acid (32 ml)—water (6.5 ml)—sulfuric acid (0.97 ml) were addediodine (1.65 g) and periodic acid dihydrate (740 mg) at roomtemperature, and the mixture was heated to 60-80° C. for 5 hours. Afterbeing allowed to cool to room temperature, the mixture was partitionedbetween hexane/ethyl acetate and water. The organic layer was separated,washed successively with water, sodium sulfite solution, water andbrine, dried over magnesium sulfate, and filtered. The filtrate wasconcentrated and the residue was recrystallized from diisopropyl ether(44 ml) to give2,2,2-trifluoro-N-[(1R)-2-(4-iodophenyl)-1-methylethyl]acetamide (2.15g) as a colorless needle.

[0301] NMR (CDCl₃, δ): 1.21 (3H, d, J=7 Hz), 2.74 (1H, dd, J=14, 7 Hz),2.85 (1H, dd, J=14, 6 Hz), 4.26 (1H, m), 6.04 (1H, br s), 6.92 (2H, d,J=8 Hz), 7.65 (2H, d, J=8 Hz)

[0302] (+)ESI-MS (m/z): 380 (M+Na)⁺

[0303] Preparation 33

[0304] The following compound was obtained according to a similar mannerto that of Preparation 32.2,2,2-Trifluoro-N-[3-(4-iodophenyl)propyl]acetamide

[0305] NMR (CDCl₃, δ): 1.90 (2H, quintet, J=7 Hz), 2.62 (2H, t, J=7 Hz),3.38 (2H, q, J=7 Hz), 6.26 (1H, br s), 6.93 (2H, d, J=8 Hz), 7.62 (2H,d, J=8 Hz)

[0306] (+)ESI-MS (m/z): 380 (M+Na)⁺

[0307] Preparation 34

[0308] To a mixture of 3-(4-hydroxyphenyl)propanoic acid (15.0 g),(1R)-2-amino-1-(3-chlorophenyl)ethanol hydrochloride (18.8 g), and1-hydroxybenzotriazole (14.6 g) in N,N-dimethylformamide (100 ml) wasadded 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (26.0g), and the mixture was stirred at room temperature for 3 hours. Themixture was partitioned between ethyl acetate and water. The organiclayer was separated, washed successively with sodium bicarbonatesolution and brine, dried over magnesium sulfate, and filtered. Thefiltrate was concentrated and the residue was purified by columnchromatography (silica gel, hexane/ethyl acetate) to giveN-[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]-3-(4-hydroxyphenyl)propanamide(11.61 g) as a white amorphous powder.

[0309] MS (m/z): 320 (M+H)

[0310] Preparation 35

[0311] To a solution ofN-[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]-3-(4-hydroxyphenyl)propanamide(11.61 g) in tetrahydrofuran (70 ml) was added borane-methyl sulfidecomplex (10M, 11.9 ml) at 0° C., and the mixture was heated to 80° C.for 1 hour. After being allowed to cool to room temperature, the mixturewas added 2N hydrochloric acid (20 ml) at 0° C. The mixture was heatedto 80° C. for 1 hour. After being allowed to cool to room temperature,the mixture was added 1N sodium hydroxide (40 ml) and di-tert-butyldicarbonate (8.72 g) and stirred for 1 hour at room temperature. Themixture was partitioned between hexane/ethyl acetate and water. Theorganic layer was separated, washed successively with water, sodiumsulfite solution, water and brine, dried over magnesium sulfate, andfiltered. The filtrate was concentrated and the residue was purified bycolumn chromatography (silica gel, hexane/ethyl acetate) to givetert-butyl[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl][3-(4-hydroxyphenyl)propyl]carbamate(11.36 g) as a white powder.

[0312] MS (m/z): 406 (M+H)

[0313] Preparation 36

[0314] A mixture of methyl4′-[2-[[(benzyloxy)carbonyl]-amino]ethyl]-2-methyl-1,1′-biphenyl-4-carboxylate(650 mg), ammonium formate (500 mg) and palladium on carbon powder (400mg) in methanol (10 ml) and water (1.0 ml) was refluxed for 2 hours. Thereaction mixture was filtrated and poured into water and extracted withchloroform. The organic layer was washed with brine, dried overmagnesium sulfate and evaporated to give methyl4′-(2-aminoethyl)-2-methyl-1,1′-biphenyl-4-carboxylate (380 mg).

[0315] (+)ESI-MS (m/z): 270 (M+H)⁺

[0316] Preparation 37

[0317] The following compounds were obtained according to a similarmanner to that of Preparation 36.

[0318] (1) Ethyl 4′-(2-aminoethyl)-2-methoxy-1,1′-biphenyl-4-carboxylate

[0319] MS (m/z): 300 (M+H)

[0320] (2) tert-Butyl[2-(4-hydroxyphenyl)ethyl][(2R)-2-hydroxy-2-(3-pyridyl)ethyl]carbamtate

[0321] MS (m/z): 359 (M+H)

[0322] Preparation 38

[0323] The following compound was obtained according to a similar mannerto that of Example 14.

[0324] tert-Butyl[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl][2-(4′-formyl-2′,3′-dimethyl-1,1′-biphenyl-4-yl)ethyl]carbamate

[0325] (+)ESI-MS (m/z): 530 (M+Na)⁺

EXAMPLE 14

[0326] To a solution of tert-butyl[2-(4-bromophenyl)ethyl]-[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]carbamate(365 mg) in 1,2-dimethoxyethane (6 ml) was added[4-(ethoxycarbonyl)-2-methoxyphenyl]boronic acid (216 mg),tetrakis(triphenylphosphine)palladium (46 mg) and aqueous solution ofsodium carbonate (2M, 0.85 ml), and the mixture was stirred at 80° C.for 4 hours under nitrogen. The mixture was diluted with ethyl acetateand water. The organic layer was separated, washed with brine, driedover magnesium sulfate and evaporated under reduced pressure. Theresidue was purified by column chromatography on silica gel(hexane/ethyl acetate=2/1) to give ethyl4′-[2-[(tert-butoxycarbonyl)[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]-amino]ethyl]-2-methoxy-1,1′-biphenyl-4-carboxylate(222 mg).

[0327] MS (m/z): 554 (M+H)⁺

EXAMPLE 15

[0328] The following compounds were obtained according to a similarmanner to that of Example 14.

[0329] (1)4′-[(2R)-2-[[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino]propyl]-3-methoxy-1,1′-biphenyl-4-carboxylicAcid Hydrochloride

[0330] NMR (DMSO-d₆, δ): 1.14 (3H, d, J=6.4 Hz), 2.8-3.8 (5H, m), 3.92(3H, s), 5.0-5.3 (1H, m), 6.3-6.4 (1H, m), 7.2-7.8 (10H, m), 8.13 (1H,br s), 8.85 (1H, br s), 9.42 (1H, br s)

[0331] MS (m/z): 440 (M+H)

[0332] (2)4′-[(2R)-2-[[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]-amino]propyl]-2-methoxy-1,1′-biphenyl-4-carboxylicAcid Hydrochloride

[0333] NMR (DMSO-d₆, δ): 1.17 (3H, d, J=6.4 Hz), 2.8-3.8 (5H, m), 3.83(3H, s), 5.0-5.2 (1H, m), 6.3-6.4 (1H, m), 7.2-7.8 (10H, m), 8.11 (1H,br s), 8.86 (1H, br s), 9.37 (1H, br s)

[0334] MS (m/z): 440 (M+H)

[0335] (3)4′-[(2R)-2-[[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]-amino]propyl]-2-methyl-1,1′-biphenyl-4-carboxylicAcid Hydrochloride

[0336] NMR (DMSO-d₆, δ): 1.17 (3H, d, J=6.4 Hz), 2.28 (3H, s), 2.8-3.8(5H, m), 5.0-5.3 (1H, m), 6.3-6.4 (1H, m) 7.2-7.6 (8H, m), 7.7-7.9 (2H,m), 8.11 (1H, br s), 8.86 (1H, br s), 9.39 (1H, br δ)

[0337] MS (m/z): 424 (M+H)

[0338] (4)4′-[(2R)-2-[[(2S)-2-(3-Chlorophenyl)-2-hydroxyethyl]-amino]propyl]-3-methoxy-1,1′-biphenyl-4-carboxylicAcid Hydrochloride

[0339] NMR (DMSO-d₆, δ): 1.16 (3H, d, J=6.4 Hz), 2.8-3.8 (5H, m), 3.91(3H, s), 5.0-5.3 (1H, m), 6.3-6.4 (1H, m), 7.2-7.8 (11H, m), 8.77 (1H,br s), 9.13 (1H, br δ)

[0340] MS (m/z): 440 (M+H)

[0341] (5)4′-[(2R)-2-[[(2R)-2-Phenyl-2-hydroxyethyl]amino]-propyl]-3-methoxy-1,1′-biphenyl-4-carboxylicAcid Hydrochloride

[0342] NMR (DMSO-d₆, δ): 1.15 (3H, d, J=6.4 Hz), 2.8-3.8 (5H, m), 3.92(3H, s), 5.0-5.2 (1H, m), 6.3-6.4 (1H, m), 7.2-7.6 (9H, m), 7.7-7.9 (3H,m), 8.81 (1H, br s), 9.31 (1H, br s)

[0343] MS (m/z): 406 (M+H)

[0344] (6)4′-[(2R)-2-[[(2R)-2-Phenyl-2-hydroxyethyl]amino]-propyl]-2-methyl-1,1′-biphenyl-4-carboxylicAcid Hydrochloride

[0345] NMR (DMSO-d₆, δ): 1.17 (3H, d, J=6.4 Hz), 2.28 (3H, s), 2.8-3.8(5H, m), 5.0-5.2 (1H, m), 6.3-6.4 (1H, m), 7.2-7.6 (9H, m), 7.7-7.9 (3H,m), 8.81 (1H, br δ), 9.24 (1H, br s)

[0346] MS (m/z): 390 (M+H)

[0347] (7)4′-[(2R)-2-[[(2S)-2-Phenyl-2-hydroxyethyl]amino]-propyl]-2-methyl-1,1′-biphenyl-4-carboxylicAcid Hydrochloride

[0348] NMR (DMSO-d₆, δ): 1.19 (3H, d, J=6.4 Hz), 2.27 (3H, s), 2.8-3.8(5H, m), 5.0-5.2 (1H, m), 6.2-6.3 (1H, m), 7.2-7.6 (9H, m), 7.7-7.9 (3H,m), 8.80 (1H, br s), 9.35 (1H, br s)

[0349] MS (m/z): 390 (M+H)

[0350] (8)4′-[(2R)-2-[[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]-amino]propyl]-3-isopropyloxy-1,1′-biphenyl-4-carboxylicAcid Hydrochloride

[0351] NMR (DMSO-d₆, δ): 1.14 (3H, d, J=6.4 Hz), 1.30 (6H, d, J=5.8 Hz),2.8-3.8 (5H, m), 4.6-4.9 (1H, m), 5.0-5.3 (1H, m), 6.2-6.4 (1H, m),7.2-7.8 (1H, m), 8.82 (1H, br s), 9.24 (1H, br s)

[0352] MS (m/z): 468 (M+H)

[0353] (9)4′-[(2R)-2-[[(2R)-2-Phenyl-2-hydroxyethyl]amino]-propyl]-3-isopropyloxy-1,1′-biphenyl-4-carboxylicAcid Hydrochloride

[0354] NMR (DMSO-d₆, δ): 1.12 (3H, d, J=6.4 Hz), 1.30 (6H, d, J=5.8 Hz),2.8-3.8 (5H, m), 4.6-4.9 (1H, m), 5.0-5.3 (1H, m), 6.2-6.4 (1H, m),7.2-7.8 (12H, m), 8.82 (1H, br s)

[0355] MS (m/z): 434 (M+H)

[0356] (10)4′-[(2R)-2-[[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]-amino]propyl]-3-cyclohexyloxy-1,1′-biphenyl-4-carboxylicAcid Hydrochloride

[0357] NMR (DMSO-d₆, δ): 1.14 (3H, d, J=6.4 Hz), 1.2-2.0 (10H, m),2.8-3.8 (5H, m), 4.65 (1H, m), 5.0-5.2 (1H, m), 6.3-6.4 (1H, m), 7.2-7.9(11H, m), 8.79 (1H, br s), 9.10 (1H, br s)

[0358] MS (m/z): 508 (M+H)

[0359] (11)4′-[(2R)-2-[[(2R)-2-Phenyl-2-hydroxyethyl]amino]-propyl]-3-cyclohexyloxy-1,1′-biphenyl-4-carboxylicAcid Hydrochloride

[0360] NMR (DMSO-d₆, δ): 1.14 (3H, d, J=6.4 Hz), 1.2-2.0 (10H, m),2.8-3.8 (5H, m), 4.65 (1H, m), 4.9-5.1 (1H, m), 6.23 (1H, m), 7.1-7.9(12H, m)

[0361] MS (m/z): 474 (M+H)

[0362] (12) Methyl4′-[2-[(tert-butoxycarbonyl)[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]-3-methoxy-1,1′-biphenyl-4-carboxylate

[0363] (+)ESI-MS (m/z): 562 (M+Na)⁺

[0364] (13) Methyl4′-[2-[(tert-butoxycarbonyl)[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]-2-chloro-1,1′-biphenyl-4-carboxylate

[0365] (+)ESI-MS (m/z): 544 (M+H)⁺

EXAMPLE 16

[0366] To a solution of4-[2-[(tert-butoxycarbonyl)[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]phenyltrifluoromethanesulfonate (300 mg) in 1,2-dimethoxyethane (5 ml) wasadded [3-fluoro-4-(methoxycarbonyl)phenyl]boronic acid (125 mg),tetrakis(triphenylphosphine)palladium (53 mg) and aqueous solution ofsodium carbonate (2M, 0.6 ml), and the mixture was stirred at 80° C. for2 hours under nitrogen. The mixture was diluted with ethyl acetate andwater. The organic layer was separated, washed with brine, dried overmagnesium sulfate and evaporated under reduced pressure. The residue waspurified by column chromatography on silica gel (hexane/ethylacetate=3/1) to give methyl4′-[2-[(tert-butoxycarbonyl)[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]-3-fluoro-1,1′-biphenyl-4-carboxylate(230 mg).

[0367] (+)ESI-MS (m/z): 528 (M+H)⁺

EXAMPLE 17

[0368] The following compound was obtained according to a similar mannerto that of Example 16.

[0369] Methyl4′-[2-[(tert-butoxycarbonyl)[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]-3-methyl-1,1′-biphenyl-4-carboxylate

[0370] (+)ESI-MS (m/z): 546 (M+Na)⁺

EXAMPLE 18

[0371] To a solution of ethyl4′-[2-[(tert-butoxycarbonyl)-[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]-2-methoxy-1,1′-biphenyl-4-carboxylate(220 mg) in ethanol (2.0 ml) was added 1N aqueous sodium hydroxidesolution (1.2 ml), and the mixture was stirred at 40° C. for 3 hours.The solvent was removed by evaporation, and the aqueous solution wasacidified with 1N hydrochloric acid and extracted with ethyl acetate (30ml×2). The combined organic layers were washed with water and brine,dried over magnesium sulfate and evaporated under reduced pressure togive a benzoic acid product. To a solution of the product intetrahydrofuran (1.5 ml) was added 4N hydrochloride in dioxane (1.0 ml),and the mixture was stirred at room temperature for 12 hours. Theresultant solid was collected by filtration and dried to give4′-[2-[[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]-ethyl]-2-methoxy-1,1′-biphenyl-4-carboxylicacid hydrochloride (83 mg).

[0372] NMR (DMSO-d₆, δ): 3.02-3.27 (6H, m), 3.82 (3H, s), 4.98-5.02 (1H,m), 6.35 (1H, br), 7.30-7.64 (1H, m), 9.05 (1H, br)

[0373] (−)ESI-MS (m/z): 424 (M−HCl−H)⁻

EXAMPLE 19

[0374] The following compounds were obtained according to a similarmanner to that of Example 18.

[0375] (1)4′-[2-[[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino]-ethyl]-3-methoxy-1,1′-biphenyl-4-carboxylicAcid Hydrochloride

[0376] NMR (DMSO-d₆, δ): 3.01-3.34 (6H, m), 3.92 (3H, s), 5.02-5.06 (1H,m), 6.37 (1H, br), 7.26-7.48 (9H, m), 7.74 (2H, d, J=7.9 Hz), 9.25 (1H,br)

[0377] (−)ESI-MS (m/z): 424 (M−HCl−H)⁻

[0378] (2)2-Chloro-4′-[2-[[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]-1,1′-biphenyl-4-carboxylicAcid Hydrochloride

[0379] NMR (DMSO-d₆, δ): 3.01-3.34 (6H, m), 4.99-5.03 (1H, m), 6.36 (1H,br), 7.37-7.55 (9H, m), 7.93-8.03 (2H, m), 9.10 (1H, br)

[0380] (−)ESI-MS (m/z): 424 (M−HCl−H)⁻

[0381] (3)4′-[2-[[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino]-ethyl]-3-fluoro-1,1′-biphenyl-4-carboxylicAcid Hydrochloride

[0382] NMR (DMSO-d₆, δ): 3.01-3.33 (6H, m), 4.98-5.03 (1H, m), 6.34 (1H,br), 7.35-7.47 (6H, m), 7.61-7.98 (5H, m), 9.10 (1H, br)

[0383] (−)ESI-MS (m/z): 412 (M−HCl−H)⁻

[0384] (4)4′-[2-[[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino]-ethyl]-3-methyl-1,1′-biphenyl-4-carboxylicAcid Hydrochloride

[0385] NMR (DMSO-d₆, δ): 2.60 (3H, s), 3.01-3.34 (6H, m), 4.98-5.02 (1H,m), 6.34 (1H, br), 7.36-7.60 (8H, m), 7.72 (2H, d, J=8.0 Hz), 7.91 (1H,d, J=8.0 Hz), 9.25 (1H, br)

[0386] (−)ESI-MS (m/z): 408 (M−HCl−H)⁻

EXAMPLE 20

[0387] To a solution of tert-butyl[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl][2-(4′-formyl-2′,3′-dimethyl-1,1′-biphenyl-4-yl)ethyl]carbamatein acetonitrile (2.5 ml) and pH 4 buffer solution (sodiumdihydrogenphosphate) (1.3 ml) was added 30% hydrogen peroxide solution(60 μl) and 80% sodium chlorite (128 mg) below 10° C. The reactionmixture was stirred at 40° C. for 1.5 hours. The mixture was dilutedwith ethyl acetate, washed with water and brine, dried over magnesiumsulfate and evaporated under reduced pressure to give a benzoic acidproduct. To a solution of the product in tetrahydrofuran (1.0 ml) wasadded 4N hydrochloride in dioxane (1.18 ml), and the mixture was stirredat room temperature for 12 hours. The resultant solid was collected byfiltration and dried to give4′-[2-[[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]-2,3-dimethyl-1,1′-biphenyl-4-carboxylicacid hydrochloride (140 mg).

[0388] NMR (DMSO-d₆, δ): 2.14 (3H, s), 2.45 (3H, s), 3.00-3.34 (6H, m),4.99-5.03 (1H, m), 6.34 (1H, br), 7.07 (1H, d, J=8.0 Hz), 7.05-7.59 (9H,m), 9.25 (1H, br)

[0389] (−)ESI-MS (m/z): 422 (M−HCl−H)

EXAMPLE 21

[0390] A solution of ethyl4′-(3-aminopropyl)-1,1′-biphenyl-4-carboxylate (200 mg), and2-chloro-5-[(2R)-2-oxiranyl]-pyridine (71.5 mg) in ethanol (10 ml) wasrefluxed for 18 hours. The mixture was evaporated in vacuo. The residuewas purified by column chromatography on silica gel(chloroform:methanol=100:1) to give ethyl4′-[3-[[(2R)-2-(6-chloro-3-pyridyl)-2-hydroxyethyl]amino]propyl]-1,1′-biphenyl-4-caroxylate(96 mg) as a colorless foam.

[0391] MS (m/z): 439 (M+H)⁻

EXAMPLE 22

[0392] The following compounds were obtained according to a similarmanner to that of Example 21.

[0393] (1) Methyl4′-[2-[[(2R)-2-(6-chloro-3-pyridyl)-2-hydroxyethyl]amino]ethyl]-2-methyl-1,1′-biphenyl-4-carboxylate

[0394] (+)ESI-MS (m/z): 425 (M+H)⁺

[0395] (2) Ethyl4′-[2-[[(2R)-2-(6-chloro-3-pyridyl)-2-hydroxyethyl]amino]ethyl]-2-methoxy-1,1′-biphenyl-4-carboxylate

[0396] MS (m/z): 454 (M⁺)

EXAMPLE 23

[0397] To a solution of ethyl4′-[3-[[(2R)-2-(6-chloro-3-pyridyl)-2-hydroxyethyl]amino]propyl]-1,1′-biphenyl-4-carboxylate(96 mg) in tetrahydrofuran (3.5 ml) was added di-tert-butyl dicarbonate(53 mg), and the mixture was stirred at room temperature for 30 minutesand then evaporated. To the residue were added 1N sodium hydroxidesolution (0.5 ml) and methanol (0.5 ml), and was stirred for 2 hours atroom temperature. The residue was diluted with ethyl acetate andsaturated aqueous sodium bicarbonate solution. The organic layer wasseparated, washed with brine, dried over magnesium sulfate andevaporated. The residue was purified by column chromatography on silicagel (hexane/ethyl acetate=1/1) to give4′-[3-[(tert-butoxycarbonyl)[(2R)-2-(6-chloro-3-pyridyl)-2-hydroxyethyl]-amino]propyl]-1,1′-biphenyl-4-carboxylicacid (100 mg) as a colorless foam.

[0398] MS (m/z): 512 (M+H)

EXAMPLE 24

[0399] The following compounds were obtained according to a similarmanner to that of Example 23.

[0400] (1)4′-[2-[(tert-Butoxycarbonyl)[(2R)-2-(6-chloro-3-pyridyl)-2-hydroxyethyl]amino]ethyl]-2-methyl-1,1′-biphenyl-4-carboxylicAcid

[0401] (+)ESI-MS (m/z): 509 (M−H)⁻

[0402](2)-4′-[2-[(tert-Butoxycarbonyl)[(2R)-2-(6-chloro-3-pyridyl)-2-hydroxyethyl]amino]ethyl]-2-methoxy-1,1′-biphenyl-4-carboxylicAcid

[0403] MS (m/z): 527 (M+H)

EXAMPLE 25

[0404]4′-[3-[(tert-Butoxycarbonyl)[(2R)-2-(6-chloro-3-pyridyl)-2-hydroxyethyl]amino]propyl]-1,1′-biphenyl-4-carboxylicacid (100 mg), ammonium formate (50 mg) and palladium on carbon powder(30 mg) in methanol (5 ml) and water (1.0 ml) was refluxed for 30minutes. The reaction mixture was filtrated and poured into water andextracted with ethyl acetate. The organic layer was washed with brine,dried over magnesium sulfate, and evaporated in vacuo. A mixture of theresidue was chromatographed (chloroform-methanol) over silica gel togive4′-[3-[(tert-butoxycarbonyl)[(2R)-2-hydroxy-2-(3-pyridyl)ethyl]amino]-propyl]-1,1′-biphenyl-4-carboxylicacid (90 mg) as a colorless foam.

[0405] MS (m/z): 477 (M+H)

EXAMPLE 26

[0406] The following compounds were obtained according to a similarmanner to that of Example 25.

[0407] (1)4′-[2-[(tert-Butoxycarbonyl)[(2R)-2-hydroxy-2-(3-pyridyl)ethyl]amino]ethyl]-2-methyl-1,1′-biphenyl-4-carboxylicAcid

[0408] (+)ESI-MS (m/z): 475 (M−H)⁻

[0409] (2)4′-[2-[(tert-Butoxycarbonyl)[(2R)-2-hydroxy-2-(3-pyridyl)ethyl]amino]ethyl]-2-methoxy-1,1′-biphenyl-4-carboxylicAcid

[0410] MS (m/z): 493 (M+H)

[0411] (3)4′-[3-[(tert-Butoxycarbonyl)[(2R)-2-hydroxy-2-(3-pyridyl)ethyl]amino]propyl]-2-methoxy-1,1′-biphenyl-4-carboxylicAcid

[0412] MS (m/z): 507 (M+H)

[0413] (4)4′-[(2R)-2-[(tert-Butoxycarbonyl)[(2R)-2-hydroxy-2-(3-pyridyl)ethyl]amino]propyl]-1,1′-biphenyl-4-carboxylicAcid

[0414] MS (m/z) 477 (M+H)

EXAMPLE 27

[0415] A solution of tert-butyl4′-[3-[(tert-butoxycarbonyl)-[(2R)-2-hydroxy-2-(3-pyridyl)ethyl]amino]propyl]-1,1′-biphenyl-4-carboxylicacid (90 mg) and 4N hydrochloride in dioxane (5.0 ml) was stirred atroom temperature for 24 hours. The resultant solid was collected byfiltration and dried to give4′-[3-[[(2R)-2-hydroxy-2-(3-pyridyl)ethyl]-amino]propyl]-1,1′-biphenyl-4-carboxylicacid dihydrochloride (80 mg) as a white solid.

[0416] NMR (DMSO-d₆, δ): 2.90-3.90 (8H, m), 5.10-5.20 (1H, m), 7.35 (1H,d, J=8 Hz), 7.65-7.85 (6H, m), 8.05 (1H, d, J=8 Hz), 8.25 (1H, d, J=8Hz), 8.70-8.85 (2H, m)

[0417] MS (m/z): 377 (M+H)

EXAMPLE 28

[0418] The following compounds were obtained according to a similarmanner to that of Example 27.

[0419] (1)4′-[2-[[(2R)-2-Hydroxy-2-(3-pyridyl)ethyl]amino]ethyl]-2-methyl-1,1′-biphenyl-4-carboxylicAcid dihydrochloride

[0420] NMR (DMSO-d₆, δ): 3.10-3.80 (6H, m), 3.90 (3H, s), 5.10-5.20 (1H,m), 7.40-7.70 (7H, m), 7.8-7.90 (1H, m), 8.25 (1H, d, J=8 Hz), 8.70-8.85(2H, m)

[0421] (−)ESI-MS (m/z): 375 (M−2HCl-H)⁻

[0422] (2)4′-[2-[[(2R)-2-Hydroxy-2-(3-pyridyl)ethyl]amino]ethyl]-2-methoxy-1,1′-biphenyl-4-carboxylicAcid dihydrochloride

[0423] NMR (DMSO-d₆, δ): 3.10-3.80 (6H, m), 3.90 (3H, s), 5.10-5.20 (1H,m), 7.40-7.70 (7H, m), 7.80-7.90 (1H, m), 8.25 (1H, d, J=8 Hz),8.70-8.85 (2H, m)

[0424] MS (m/z): 393 (M+H)

[0425] (3)4′-[3-[[(2R)-2-Hydroxy-2-(3-pyridyl)ethyl]amino]-propyl]-2-methoxy-1,1′-biphenyl-4-carboxylicAcid dihydrochloride

[0426] NMR (DMSO-d₆, δ): 2.90-3.90 (8H, m), 3.95 (3H, s), 5.10-5.20 (1H,m), 7.35 (1H, d, J=8 Hz), 7.65-7.85 (6H, m), 8.05 (1H, d, J=8 Hz), 8.25(1H, d, J=8 Hz), 8.70-8.85 (2H, m)

[0427] MS (m/z): 407 (M+H)

[0428] (4)2-Chloro-4′-[2-[[(2R)-2-hydroxy-2-(3-pyridyl)ethyl]-amino]ethyl]-1,1′-biphenyl-4-carboxylicAcid dihydrochloride

[0429] NMR (DMSO-d₆, δ): 3.10-3.80 (6H, m), 5.10-5.20 (1H, m), 7.40-7.70(7H, m), 7.90-8.10 (2H, m), 8.70-8.85 (2H, m)

[0430] MS (m/z): 397 (M+H)

[0431] (5)4′-[(2R)-2-[[(2R)-2-Hydroxy-2-(3-pyridyl)ethyl]amino]-propyl]-1,1′-biphenyl-4-carboxylicAcid dihydrochloride

[0432] NMR (DMSO-d₆, δ): 1.70 (3H, d, J=6 Hz), 3.30-3.90 (6H, m),5.10-5.20 (1H, m), 7.40-7.70 (7H, m), 7.80-7.90 (1H, m), 8.25 (1H, d,J=8 Hz), 8.70-8.85 (2H, m)

[0433] MS (m/z): 377 (M+H)

[0434] (6)4′-[3-[[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino]-propyl]-2-methyl-1,1′-biphenyl-4-carboxylicAcid Hydrochloride

[0435] NMR (DMSO-d₆, δ): 2.00-2.15 (2H, m), 2.30 (3H, s), 2.60-3.30 (6H,m), 5.00-5.10 (1H, m), 7.20-7.60 (9H, m), 7.75-7.90 (2H, m)

[0436] MS (m/z): 424 (M+H)

EXAMPLE 29

[0437] The following compounds were obtained according to a similarmanner to that of Example 23.

[0438] (1) Ethyl4′-[3-[(tert-butoxycarbonyl)[(2R)-2-(6-chloro-3-pyridyl)-2-hydroxyethyl]amino]propyl]-2-methoxy-1,1′-biphenyl-4-carboxylate

[0439] MS (m/z): 569 (M+H)

[0440] (2) Methyl4′-[2-[(tert-butoxycarbonyl)[(2R)-2-hydroxy-2-(3-pyridyl)ethyl]amino]ethyl]-2-chloro-1,1′-biphenyl-4-carboxylate

[0441] MS (m/z): 512 (M+H)

[0442] (3) Methy4′-[(2R)-2-[(tert-butoxycarbonyl)[(2R)-2-(6-chloro-3-pyridyl)-2-hydroxyethyl]amino]propyl]-1,1′-biphenyl-4-carboxylate

[0443] MS (m/z): 524 (M+H)

[0444] (4) Methyl4′-[3-[(tert-butoxycarbonyl)[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]propyl]-2-methyl-1,1′-biphenyl-4-carboxylate

[0445] MS (m/z): 538 (M+H)

[0446] (5)4′-[(2R)-2-[[(2R)-2-Hydroxy-2-(3-pyridyl)ethyl]amino]-propyl]-3-methoxy-1,1′-biphenyl-4-carboxylicAcid dihydrochloride

[0447] NMR (DMSO-d₆, δ): 1.14 (3H, d, J=6.4 Hz), 2.8-3.8 (5H, m), 3.92(3H, s), 5.1-5.3 (1H, m), 7.2-7.5 (4H, m), 7.7-7.9 (4H, m), 8.2-8.4 (1H,m), 8.8-9.0 (2H, m), 9.36 (1H, br s)

[0448] MS (m/z): 407 (M+H)

[0449] (6)4′-[(2R)-2-[[(2R)-2-Hydroxy-2-(3-pyridyl)ethyl]amino]-propyl]-2-methoxy-1,1′-biphenyl-4-carboxylicAcid dihydrochloride

[0450] NMR (DMSO-d₆, δ): 1.14 (3H, d, J=6.4 Hz), 2.8-3.8 (5H, m), 3.83(3H, s), 5.1-5.3 (1H, m), 7.2-7.8 (7H, m), 7.8-8.0 (1H, m), 8.2-8.5 (1H,m), 8.7-9.0 (2H, m), 9.02 (1H, br s), 9.36 (1H, br s)

[0451] MS (m/z): 407 (M+H)

[0452] (7)4′-[(2R)-2-[[(2R)-2-Hydroxy-2-(3-pyridyl)ethyl]amino]-propyl]-2-methyl-1,1′-biphenyl-4-carboxylicAcid dihydrochloride

[0453] NMR (DMSO-d₆, δ): 1.19 (3H, d, J=6.4 Hz), 2.48 (3H, s), 2.8-3.8(5H, m), 5.1-5.3 (1H, m), 7.2-7.5 (5H, m), 7.8-8.0 (3H, m), 8.37 (1H, d,J=8.2 Hz), 8.78 (1H, d, J=4.6 Hz), 8.87 (1H, s), 9.04 (1H, br s), 9.35(1H, br s)

[0454] MS (m/z): 391 (M+H)

[0455] (8)4′-[(2R)-2-[[(2R)-2-Hydroxy-2-(3-pyridyl)ethyl]amino]-propyl]-3-methyl-1,1′-biphenyl-4-carboxylicAcid dihydrochloride

[0456] NMR (DMSO-d₆, δ): 1.19 (3H, d, J=6.4 Hz), 2.60 (3H, s), 2.8-3.8(5H, m), 5.1-5.3 (1H, m), 7.2-8.0 (8H, m), 8.37 (1H, d, J=8.2 Hz), 8.79(1H, d, J=4.6 Hz), 8.87 (1H, s), 9.05 (1H, br s), 9.35 (1H, br s)

[0457] MS (m/z): 391 (M+H)

[0458] (9)4′-[(2R)-2-[[(2R)-2-Hydroxy-2-(3-pyridyl)ethyl]amino]-propyl]-3-isopropyloxy-1,1′-biphenyl-4-carboxylicAcid dihydrochloride

[0459] NMR (DMSO-d₆, δ): 1.19 (3H, d, J=6.4 Hz), 1.31 (6H, d, J=6.0 Hz),2.8-3.8 (5H, m), 4.6-4.9 (1H, m), 5.1-5.3 (1H, m), 7.2-7.5 (4H, m),7.6-8.0 (4H, m), 8.37 (1H, d, J=8.2 Hz), 8.80 (1H, d, J=4.6 Hz), 8.88(1H, s), 9.02 (1H, br s), 9.35 (1H, br s)

[0460] MS (m/z): 435 (M+H)

[0461] (10)4′-[(2R)-2-[[(2S)-2-Hydroxy-2-(3-pyridyl)ethyl]amino]-propyl]-1,1′-biphenyl-4-carboxylicAcid dihydrochloride

[0462] NMR (DMSO-d₆, δ): 1.19 (3H, d, J=6.4 Hz), 2.8-3.8 (5H, m),5.1-5.3 (1H, m), 7.2-8.1 (8H, m), 8.57 (1H, d, J=7.8 Hz), 8.81 (1H, d,J=4.6 Hz), 8.90 (1H, s), 9.10 (1H, br s), 9.56 (1H, br s)

[0463] MS (m/z): 357 (M−H)

[0464] (11)4′-[(2R)-2-[[(2S)-2-Hydroxy-2-(6-chloro-3-pyridyl)ethyl]amino]propyl]-1,1′-biphenyl-4-carboxylicAcid dihydrochloride

[0465] NMR (DMSO-d₆, δ): 1.17 (3H, d, J=6.4 Hz), 2.8-3.8 (5H, m),5.1-5.3 (1H, m), 7.39 (2H, d, J=8.0 Hz), 7.58 (1H, d, J=8.0 Hz), 7.6-8.2(7H, m), 8.48 (1H, d, J=2.4 Hz), 8.86 (1H, br s), 9.22 (1H, br s)

[0466] MS (m/z): 409 (M−H)

[0467] (12)4′-[(2R)-2-[[(2R)-2-Hydroxy-2-(6-chloro-3-pyridyl)ethyl]amino]propyl]-1,1′-biphenyl-4-carboxylicAcid dihydrochloride

[0468] NMR (DMSO-d₆, δ): 1.16 (3H, d, J=6.4 Hz), 2.8-3.8 (5H, m),5.1-5.3 (1H, m), 7.38 (2H, d, J=8.0 Hz), 7.58 (1H, d, J=8.0 Hz), 7.6-8.2(7H, m), 8.49 (1H, d, J=2.4 Hz), 8.86 (1H, br s), 9.45 (1H, br s)

[0469] MS (m/z): 409 (M−H)

[0470] (13)4′-[(2R)-2-[[(2R)-2-Hydroxy-2-(3-pyridyl)ethyl]amino]-propyl]-3-cyclohexyloxy-1,1′-biphenyl-4-carboxylicAcid dihydrochloride

[0471] NMR (DMSO-d₆, δ): 1.15 (3H, d, J=6.4 Hz), 1.2-2.0 (10H, m),2.7-3.8 (5H, m), 4.65 (1H, m), 5.31 (1H, m), 7.2-7.5 (5H, m), 7.6-7.8(2H, m), 7.9-8.0 (1H, m), 8.45 (1H, m), 8.82 (1H, d, J=2.6 Hz), 8.90(1H, s), 9.07 (1H, br s), 9.43 (1H, br s)

[0472] MS (m/z): 475 (M+H)

EXAMPLE 30

[0473] To a solution of ethyl4′-[3-[(tert-butoxycarbonyl)-[(2R)-2-(6-chloro-3-pyridyl)-2-hydroxyethyl]amino]propyl]-2-methoxy-1,1′-biphenyl-4-carboxylatein ethanol (5.0 ml) was added 1N sodium hydroxide (1.0 ml) and themixture was stirred for 2 hours at room temperature. The mixture wasdiluted with ethyl acetate and 1N hydrochloric acid. The organic layerwas separated, washed with brine, dried over magnesium sulfate andevaporated. The residue was purified by column chromatography on silicagel (hexane/ethyl acetate=1/1) to give4′-[3-[(tert-butoxycarbonyl)[(2R)-2-(6-chloro-3-pyridyl)-2-hydroxyethyl]amino]propyl]-2-methoxy-1,1′-biphenyl-4-carboxylicacid (100 mg).

[0474] MS (m/z): 541 (M+H)

EXAMPLE 31

[0475] The following compounds were obtained according to a similarmanner to that of Example 30.

[0476] (1)4′-[2-[(tert-Butoxycarbonyl)[(2R)-2-hydroxy-2-(3-pyridyl)ethyl]amino]ethyl]-2-chloro-1,1′-biphenyl-4-carboxylicAcid

[0477] MS (m/z): 497 (M+H)

[0478] (2)4′-[(2R)-2-[(tert-Butoxycarbonyl)[(2R)-2-(6-chloro-3-pyridyl)-2-hydroxyethyl]amino]propyl]-1,1′-biphenyl-4-carboxylicAcid

[0479] MS (m/z): 511 (M+H)

[0480] (3)4′-[3-[(tert-Butoxycarbonyl)[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]propyl]-1,1′-biphenyl-4-carboxylicAcid

[0481] MS (m/z): 524 (M+H)

[0482] Preparation 39

[0483] The following compound was obtained according to a similar mannerto that of Preparation 3.4.

[0484]N-[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]-3-(3-hydroxyphenyl)propanamide

[0485] MS (m/z): 320 (M+H)

[0486] Preparation 40

[0487] The following compound was obtained according to a similar mannerto that of Preparation 35.

[0488] tert-ButylN-[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]-N-[3-(3-hydroxyphenyl)propyl]carbamate

[0489] MS (m/z): 405 (M+H)

[0490] Preparation 41

[0491] The following compounds were obtained according to a similarmanner to that of Preparation 30.

[0492] (1) tert-ButylN-[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]-N-[3-[3-[[(trifluoromethyl)sulfonyl]oxy]phenyl]propyl]-carbamate

[0493] MS (m/z): 537 (M+H)

[0494] (2)4-[2-[N-(tert-Butoxycarbonyl)-N-[(2R)-2-(5-chloro-3-pyridyl)-2-hydroxyethyl]amino]ethyl]phenyltrifluoromethanesulfonate

[0495] MS (m/z): 525 (M+H)

[0496] (3) Methyl 4-[[(trifluoromethyl) sulfonyl]oxy]-1-naphthoate

[0497] MS (m/z): 358 (M+Na)

[0498] (4) Methyl [4-[[(trifluoromethyl)sulfonyl]oxy]phenyl]-acetate

[0499] NMR (DMSO-d₆, δ): 3.63(3H, s), 3.90(2H, s), 7.46(4H, s)

[0500] (5) Methyl [3-[[(trifluoromethyl)sulfonyl]oxy]phenyl]-acetate

[0501] NMR (DMSO-d₆, δ): 3.63(3H, s), 3.83(2H, s), 7.30-7.60(4H, m)

[0502] (6) 5-Hydroxy-1-naphthyl trifluoromethanesulfonate

[0503] NMR (DMSO-d₆, δ): 6.80(2H, d, J=8 Hz), 7.20(2H, t, J=8 Hz),7.50(2H, d, J=8 Hz)

[0504] (7) Ethyl 5-[[(trifluoromethyl)sulfonyl]oxy]-1-naphthoate (8)4-[2-[N-(tert-Butoxycarbonyl)-N-[(2R)-2-hydroxy-2-phenylethyl]amino]ethyl]phenyltrifluoromethane-sulfonate

[0505] MS (m/z): 490 (M+H)

[0506] (9) Methyl4-(benzyloxy)-2-[([(trifluoromethyl)sulfonyl]-oxy]benzoate

[0507] MS (m/z): 413 (M+Na)

[0508] (10) Methyl5-[[(trifluoromethyl)sulfonyl]oxy]-1,1′-biphenyl-2-carboxylate

[0509] MS (m/z): 383 (M+Na)

[0510] Preparation 42

[0511] The following compounds were obtained according to a similarmanner to that of Preparation 21.

[0512] (1)4-[2-[[(2R)-2-(5,6-Dichloro-3-pyridyl)-2-hydroxyethyl]amino]ethyl]phenol

[0513] MS (m/z): 327 (M+H)

[0514] (2) 4-[2-[[(2R)-2-Hydroxy-2-phenylethyl]amino]ethyl]phenol

[0515] MS (m/z): 258 (M+H)

[0516] Preparation 43

[0517] To a solution of4-[2-[[(2R)-2-(5,6-dichloro-3-pyridyl)-2-hydroxyethyl]amino]ethyl]phenol(850 mg) in acetic acid (15 ml) and water (1.0 ml) were addedtetramethylammonium bromide (5.2 mg) and zinc dust (509 mg), and themixture was stirred at 50° C. for 10 hours under nitrogen. The mixturewas diluted with ethyl acetate and water. The organic layer wasseparated, washed with brine, dried over magnesium sulfate andevaporated. The residue was purified by column chromatography on silicagel (hexane/ethyl acetate=2/1) to give4-[2-[[(2R)-2-(5-chloro-3-pyridyl)-2-hydroxyethyl]amino]ethyl]phenol(500 mg) as a colorless oil.

[0518] MS (m/z): 292 (M+H)

[0519] Preparation 44

[0520] The following compounds were obtained according to a similarmanner to that of Preparation 26.

[0521] (1) tert-ButylN-[(2R)-2-(5-chloro-3-pyridyl)-2-hydroxyethyl]-N-[2-(4-hydroxyphenyl)ethyl]carbamate

[0522] MS (m/z): 393 (M+H)

[0523] (2) tert-ButylN-[(2R)-2-hydroxy-2-phenylethyl]-N-[2-(4-hydroxyphenyl)ethyl]carbamate

[0524] MS (m/z): 358 (M+H)

[0525] Preparation 45

[0526] To a solution of benzamide (1.42 g) in tetrahydrofuran (50 ml)were added sodium hydride (611 mg) and 4-bromobenzenesulfonyl chloride(3.0 g), and the mixture was stirred at room temperature for 3 hours.The mixture was diluted with ethyl acetate and water. The organic layerwas separated, washed with brine, dried over magnesium sulfate andevaporated. The residue was purified by column chromatography on silicagel (hexane/ethyl acetate=2/1) to giveN-benzoyl-4-bromobenzenesulfonamide (2.1 g) as a colorless powder.

[0527] NMR (CDCl₃, δ): 7.20-8.10(8H, m)

[0528] Preparation 46

[0529] The following compounds were obtained according to a similarmanner to that of Preparation 12.

[0530] (1)2-Phenoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde

[0531] MS (m/z) 325 (M+H)

[0532] (2)N-Benzoyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide

[0533] MS (m/z): 386 (M−H)

[0534] (3) Methyl2-isobutyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate

[0535] MS (m/z): 319 (M+H)

[0536] (4) Methyl2-isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate

[0537] MS (m/z): 327 (M+Na)

[0538] (5) Methyl2-propyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate

[0539] MS (m/z): 327 (M+Na)

[0540] (6) Benzyl(1R)-1-methyl-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethylcarbamate

[0541] MS (m/z): 396 (M+H)

[0542] Preparation 47

[0543] The following compound was obtained according to a similar mannerto that of Example 1. 4-Methoxy-1-naphthoic acid

[0544] NMR (DMSO-d₆, δ): 7.00(1H, d, J=6 Hz), 7.50-7.70(2H, m),8.20-8.30(2H, m), 9.00(1H, d, J=8 Hz)

[0545] Preparation 48

[0546] Under nitrogen, 4-methoxy-1-naphthoic acid (4.33 g) indichloromethane (45 ml) was added boron tribromide (1M indichloromethane, 63 ml) dropwise at 0° C., and the mixture was stirredat the same temperature for 2 hours. The resulting mixture was pouredinto ice-cold water and the precipitate was collected by filtration. Thefilter cake was added to the mixture of water and ethyl acetate, andthen adjusted to pH 9 with 1N sodium hydroxide. After separation, theorganic layer was dried over anhydrous magnesium sulfate and evaporatedin vacuo to afford 4-hydroxy-1-naphthoic acid (2.19 g) as a colorlesspowder.

[0547] MS (m/z): 187 (M−H)

[0548] Preparation 49

[0549] To a solution of 4-hydroxy-1-naphthoic acid (2.18 g) in methanol(15 ml) was added sulfuric acid (1.0 ml), and the mixture was stirred at70° C. for 3 hours. The solution was diluted with water and ethylacetate. The organic layer was separated and washed with brine. Theextract was dried over magnesium sulfate, filtrated and concentratedunder reduced pressure. The residue was purified by columnchromatography on silica gel with ethyl acetate and hexane to givemethyl 4-hydroxy-1-naphthoate (1.64 g) as a white solid.

[0550] MS (m/z): 239 (M+Na)

[0551] Preparation 50

[0552] The following compounds were obtained according to a similarmanner to that of Preparation 16.

[0553] (1) Methyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-naphthoate

[0554] MS (m/z): 313 (M+H)

[0555] (2) Methyl[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetate

[0556] NMR (DMSO-d₆, δ): 1.66(12H, s), 3.60(3H, s), 3.70(2H, s),7.20(2H, d, J=8 Hz), 7.60(2H, d, J=8 Hz)

[0557] (3) Methyl[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetate

[0558] NMR (DMSO-d₆, δ): 3.60(3H, s), 3.82(2H, s),7.20-7.60(6H, m)

[0559] (4) MethylS-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,1′-biphenyl-2-carboxylate

[0560] MS (m/z): 361 (M+Na)

[0561] Preparation 51

[0562] To a solution of 4-bromo-2-fluorobenzaldehyde (5.0 g) indimethylsulfoxide (40 ml) were added phenol (2.78 g) and potassiumcarbonate (4.08 g), and the mixture was stirred at 100° C. for 3 hours.The solution was diluted with water and ethyl acetate. The organic layerwas separated and washed with brine. The extract was dried overmagnesium sulfate, filtrated and concentrated under reduced pressure.The residue was purified by column chromatography on silica gel withethyl acetate and hexane to give 4-bromo-2-phenoxy-1-benzaldehyde (7.3g) as a white solid.

[0563] NMR (CDCl₃, δ): 6.90-7.60(7H, m), 7.80(1H, d, J=8 Hz), 10.48(1H,s)

[0564] Preparation 52

[0565] The following compounds were obtained according to a similarmanner to that of Preparation 14.

[0566] (1) 4-(2-Methoxy-2-oxoethyl)phenylboronic Acid

[0567] MS (m/z): 193 (M−H)

[0568] (2) 3-(2-Methoxy-2-oxoethyl)phenylboronic Acid

[0569] MS (m/z): 194 (M+H)

[0570] (3) 4-[(2R)-2-[[(Benzyloxy)carbonyl]amino]propyl]-phenylboronicAcid

[0571] MS (m/z): 312 (M−H)

[0572] (4)4-[2-[N-Benzyl-N-(tert-butoxycarbonyl)amino]ethyl]-phenylboronic Acid

[0573] (−)ESI-MS m/z: 354 (M−H)

[0574] Preparation 53

[0575] The following compounds were obtained according to a similarmanner to that of Preparation 23.

[0576] (1) Methyl[4′-[(2R)-2-[[(benzyloxy)carbonyl]amino]propyl]-1,1′-biphenyl-4-yl]acetate,

[0577] MS (m/z): 418 (M+H)

[0578] (2) Ethyl5-[4-[(2R)-2-[[(benzyloxy)carbonyl]amino]propyl]-phenyl]-1-naphthoate

[0579] MS (m/z): 490 (M+Na)

[0580] (3) Methyl 5-(benzyloxy)-1,1′-biphenyl-2-carboxylate

[0581] MS (m/z): 341 (M+Na)

[0582] Preparation 54

[0583] The following compounds were obtained according to a similarmanner to that of Preparation 36.

[0584] (1) Methyl [4′-[(2R)-2-aminopropyl]-1,1′-biphenyl-4-yl]acetate

[0585] MS (m/z): 284 (M+H)

[0586] (2) Ethyl 5-[4-[(2R)-2-aminopropyl]phenyl]-1-naphthoate

[0587] MS (m/z): 356 (M+Na)

[0588] (3) Methyl 5-hydroxy-1,1′-biphenyl-2-carboxylate

[0589] MS (m/z): 251 (M+Na)

[0590] Preparation 55

[0591] To a mixture of 5-hydroxy-1-naphthyl trifluoromethane-sulfonate(8.0 g) in N,N-dimethylformamide (35 ml) and ethanol (5.0 ml) were added1,3-bis(diphenylphosphino)-propane (621 mg), palladium acetate(II) (3.7mg) and triethylamine (1.35 g), and the mixture was stirred at 100° C.for 1 hour under carbon-monoxide. The mixture was diluted with ethylacetate and water. The organic layer was separated, washed with brine,dried over magnesium sulfate and evaporated. The residue was purified bycolumn chromatography on silica gel (hexane/ethyl acetate=5/1) to giveethyl 5-hydroxy-1-naphthoate (1.7 g) as a colorless oil.

[0592] MS (m/z): 239 (M+Na)

[0593] Preparation 56

[0594] To a solution of 4-bromo-2-fluorobenzoic acid (2.0 g) intetrahydrofran (15 ml) was added 2M isobutylmagnesium bromide in diethylether (13.5 ml) dropwise on ice-cooling, and the mixture was stirred at0° C. for 1 hour. The mixture was diluted with ethyl acetate and water.The organic layer was separated, washed with brine, dried over magnesiumsulfate and evaporated. To the solution of the residue inN,N-dimethylformamide (20 ml) was added methyliodide (1.14 g) andpotassium carbonate (1.89 g), and the mixture was stirred at 20° C. for3 hours. The mixture was diluted with ethyl acetate and water. Theorganic layer was separated, washed with brine, dried over magnesiumsulfate and evaporated. The residue was purified by columnchromatography on silica gel (hexane/ethyl acetate=2/1) to give methyl4-bromo-2-isobutylbenzoate (1.5 g) as a colorless oil.

[0595] NMR (DMSO-d₆, δ): 0.80(6H, d, J=8 Hz), 1.80-2.00(1H, m), 2.80(2H,d, J=8 Hz), 3.80(3H, s), 7.40-7.80(3H, m)

[0596] Preparation 57

[0597] The following compounds were obtained according to a similarmanner to that of Preparation 56.

[0598] (1) Methyl 4-bromo-2-isopropylbenzoate

[0599] NMR (DMSO-d₆, δ): 1.20(6H, d, J=7 Hz), 3.50-3.60(1H, m), 3.83(1H,s), 7.50-7.70(3H, m)

[0600] MS (m/z): 516 (M+H)

[0601] (2) Methyl 4-bromo-2-propylbenzoate

[0602] NMR (DMSO-d₆, δ): 0.85(3H, t, J=7 Hz), 1.40-1.70(2H, m),2.80-3.00(2H, m), 3.82(3H, s), 7.60-7.70(3H, m)

[0603] Preparation 58

[0604] The following compound was obtained according to a similar mannerto that of Preparation 28.

[0605] tert-ButylN-((2R)-2-hydroxy-2-phenylethyl)-N-[(1R)-2-(4-iodophenyl)-1-methylethyl]carbamate

[0606] MS (m/z): 482 (M+H)

[0607] Preparation 59

[0608] The following compounds were obtained according to a similarmanner to that of Preparation 13.

[0609] (1) tert-ButylN-benzyl-N-[2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethyl]carbamate

[0610] (+)ESI-MS m/z: 460 (M+Na)⁺

[0611] (2)2-(1-Piperidinyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde

[0612] (+)ESI-MS m/z: 581 (M+Na)⁺

[0613] Preparation 60

[0614] To a solution of 2-(3-methoxyphenyl)ethanamine (5.6 g) indichloromethane (50 ml) was added 1M boron tribromide in dichloromethane(75 ml). The mixture was stirred at 20° C. for 16 hours and evaporatedin vacuo. To the residue, saturated sodium bicarbonate (50 ml) andtetrahydrofuran (150 ml) were added. The pH value of the mixture waskept between 7 to 8 with 1N aqueous sodium hydroxide solution. To themixture, a solution of di-tert-butyl dicarbonate (8.08 g) intetrahydrofuran (10 ml) was added, stirred at 20° C. for 1 hour. Themixture was diluted with ethyl acetate and water. The organic layer wasseparated, washed with brine, dried over magnesium sulfate andevaporated to give tert-butyl 2-(3-hydroxyphenyl)ethylcarbamate (8.2 g).

[0615] (+)ESI-MS m/z: 260 (M+Na)⁺

[0616] Preparation 61

[0617] To a solution of tert-butyl 2-(3-hydroxyphenyl)-ethylcarbamate(730 mg) and potassium carbonate (893 mg) in N,N-dimethylformamide (10ml) was added methyl 4-bromo-(3-bromomethyl)benzoate (1.52 g), and themixture was stirred at room temperature for 16 hours. The mixture waspartitioned between ethyl acetate and water. The organic layer wasseparated, washed with water and brine, dried over magnesium sulfate andevaporated under reduced pressure. The residue was purified by columnchromatography on silica gel (hexane/ethyl acetate=2/1) to give methyl4-bromo-3-[[3-[2-[(tert-butoxycarbonyl)amino]ethyl]phenoxy]methyl]-benzoate(970 mg).

[0618] (+)ESI-MS m/z: 464 (M+H)⁺

[0619] Preparation 62

[0620] To a solution of methyl4-bromo-3-[[3-[2-[(tert-butoxycarbonyl)amino]ethyl]phenoxy]methyl]benzoate(410 mg) in N,N-dimethylacetamide (4.0 ml) was addeddichlorobis(triphenylphosphine)palladium(II) (124 mg) and sodium acetate(362 mg), and the mixture was stirred at 130° C. for 1.5 hours undernitrogen. The mixture was cooled to room temperature, diluted with ethylacetate and water. The organic layer was separated, washed with brine,dried over magnesium sulfate and evaporated. The residue was purified bycolumn chromatography on silica gel (hexane/ethyl acetate=3/1) to givemethyl3-[2-[(tert-butoxycarbonyl)amino]ethyl]-6H-benzo[c]chromene-8-carboxylate(190 mg).

[0621] (+)ESI-MS m/z: 406 (M+Na)⁺

[0622] Preparation 63

[0623] The following compounds were obtained according to a similarmanner to that of Example 7.

[0624] (1) Ethyl6-[4-[2-[N-benzyl-N-(tert-butoxycarbonyl)amino]-ethyl]phenyl]nicotinate

[0625] (+)ESI-MS m/z: 461 (M+H)⁺

[0626] (2) Methyl4′-[2-[N-benzyl-N-(tert-butoxycarbonyl)amino]-ethyl]-2,6-dimethyl-1,1′-biphenyl-4-carboxylate

[0627] (+)ESI-MS m/z: 474 (M+H)⁺

[0628] Preparation 64

[0629] The following compounds were obtained according to a similarmanner to that of Example 27.

[0630] (1) Methyl 3-(2-aminoethyl)-6H-benzo[c]chromene-8-carboxylate

[0631] (+)ESI-MS m/z: 284 (M+H)⁺

[0632] (2) Ethyl 6-[4-[2-(benzylamino)ethyl]phenyl]nicotinateHydrochloride

[0633] (+)ESI-MS m/z: 361 (M+H)⁺

[0634] Preparation 65

[0635] The following compounds were obtained according to a similarmanner to that of Preparation 16.

[0636] (1)3-[2-[N-(tert-Butoxycarbonyl)-N-[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]phenyltrifluoromethanesulfonate

[0637] (+)ESI-MS m/z: 546 (M+Na)⁺

[0638] (2)4-[2-[N-(tert-Butoxycarbonyl)-N-[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]-2-methoxyphenyltrifluoromethanesulfonate

[0639] (+)ESI-MS m/z: 576 (M+Na)⁺

[0640] (3)4-[2-[N-(tert-Butoxycarbonyl)-N-[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]-2-chlorophenyltrifluoromethanesulfonate

[0641] (+)ESI-MS m/z: 581 (M+Na)⁺

[0642] Preparation 66

[0643] The following compound was obtained according to a similar mannerto that of Example 5.

[0644] Methyl4′-[2-(benzylamino)ethyl]-2,6-dimethyl-1,1′-biphenyl-4-carboxylate

[0645] (+)ESI-MS m/z: 374 (M+H)⁺

[0646] Preparation 67

[0647] To a mixture of 3-chloro-4-hydroxyphenylacetic acid (2.96 g),(1R)-2-amino-1-(3-chlorophenyl)ethanol hydrochloride (3.0 g), and1-hydroxybenzotriazole (2.14 g) in N,N-dimethylformamide (20 ml) wasadded 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (2.46 g), and themixture was stirred at room temperature for 2 hours. The mixture waspartitioned between ethyl acetate and water. The organic layer wasseparated, washed successively with sodium bicarbonate solution andbrine, dried over magnesium sulfate and evaporated under reducedpressure to give an amide product. To a tetrahydrofuran (30 ml) solutionof the product, 2M borane-dimethyl sulfide complex in tetrahydrofuran(23 ml) was added at room temperature, and the mixture was refluxed for30 minutes. To the mixture, 6N hydrochloride acid (29.5 ml) was addeddropwise below 10° C., and the mixture was stirred at room temperaturefor 3 hours. To the reaction mixture, 3N aqueous sodium hydroxidesolution (58 ml) below 10° C. was added and di-tert-butyl dicarbonate(3.46 g) was added portionally at room temperature. The pH value waskept between 7 to 8 by using 1N aqueous sodium hydroxide solution. Themixture was stirred at room temperature for 1 hour. The mixture waspartitioned between ethyl acetate and water. The organic layer wasseparated, washed brine, dried over magnesium sulfate and evaporatedunder reduced pressure. The residue was purified by columnchromatography on silica gel (hexane/ethyl acetate=2/1) to givetert-butylN-[2-(3-chloro-4-hydroxyphenyl)ethyl]-N-[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]carbamate(7.0 g).

[0648] (+)ESI-MS m/z: 448 (M+Na)⁺

[0649] Preparation 68

[0650] The following compound was obtained according to a similar mannerto that of Preparation 67.

[0651] tert-ButylN-[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]-N-[2-(4-hydroxy-3-methoxyphenyl)ethyl]carbamate

[0652] (+)ESI-MS m/z: 444 (M+Na)⁺

[0653] Preparation 69

[0654] A mixture of 4-bromo-2-fluorobenzaldehyde (3.0 g), piperidine(2.93 ml) and potassium carbonate (5.11 g) in N,N-dimethylformamide (30ml) was stirred at 100° C. for 12 hours. The mixture was cooled to roomtemperature. The mixture was partitioned between ethyl acetate andwater. The organic layer was separated, washed with water, saturatedaqueous ammonium chloride solution and brine, dried over magnesiumsulfate and evaporated under reduced pressure. The residue was purifiedby column chromatography on silica gel (hexane/ethyl acetate=9/1) togive 4-bromo-2-(1-piperidinyl)benzaldehyde (3.5 g).

[0655] (+)ESI-MS m/z: 268 (M+H)⁺

[0656] Preparation 70

[0657] The following compound was obtained according to a similar mannerto that of Example 23.

[0658] tert-Butyl N-benzyl-N-[2-(4-bromophenyl)ethyl]carbamate

[0659] (+)ESI-MS m/z: 390 (M+H)⁺

EXAMPLE 32

[0660] The following compounds were obtained according to a similarmanner to that of Example 7.

[0661] (1)4′-[(2R)-2-[[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]-amino]propyl]-3-propoxy-1,1′-biphenyl-4-carboxylicAcid Hydrochloride

[0662] NMR (DMSO-d₆, δ): 1.05(3H, t, J=7.4 Hz), 1.35(3H, d, J=6.2 Hz),1.6-1.9(2H, m), 2.8-3.8(5H, m), 4.11(2H, t, J=7.4 Hz), 5.0-5.3(1H, m),6.3-6.4(1H, m), 7.2-7.8(11H, m), 8.55(1H, br s), 9.19(1H, br s)

[0663] MS m/z: 468 (M+H)

[0664] (2)4′-[2-[[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino]-ethyl]-3-hydroxy-1,1′-biphenyl-4-carboxylicAcid Hydrochloride

[0665] NMR (DMSO-d₆, δ): 2.8-3.0(6H, m), 4.8-5.0(1H, m), 6.33(1H, m),7.0-7.9(11H, m)

[0666] MS m/z: 411 (M+H)

[0667] (3)3-Hydroxy-4′-[(2R)-2-[[(2R)-2-hydroxy-2-phenylethyl]-amino]propyl]-1,1′-biphenyl-4-carboxylicAcid Hydrochloride

[0668] NMR (DMSO-d₆, δ): 1.12(3H, d, J=6.4 Hz), 2.6-3.2(5H, m),4.9-5.1(1H, m), 6.23(1H, m), 7.2-7.9(11H, m), 8.77(1H, br s), 9.03(1H,br s)

[0669] MS m/z: 392 (M+H)

[0670] (4)3-Ethoxy-4′-[(2R)-2-[[(2R)-2-hydroxy-2-phenylethyl]-amino]propyl]-1,1′-biphenyl-4-carboxylicAcid Hydrochloride

[0671] NMR (DMSO-d₆, δ): 1.15(3H, d, J=6.4 Hz), 1.36(3H, t, J=7.0 Hz),2.6-3.2(5H, m), 4.21(2H, q, J=7.0 Hz), 4.9-5.1(1H, m), 6.23(1H, m),7.2-7.7(11H, m)

[0672] MS m/z: 418 (M−H)

[0673] (5)4¹-[(2R)-2-[[(2R)-2-Hydroxy-2-phenylethyl]amino]-propyl]-3-propoxy-1,1′-biphenyl-4-carboxylicAcid Hydrochloride

[0674] NMR (DMSO-d₆, δ): 1.03(3H, t, J=7.4 Hz), 1.12(3H, d, J=6.4 Hz),1.74(2H, m), 2.6-3.2(5H, m), 4.11(2H, q, J=7.0 Hz), 4.9-5.1(1H, m),6.23(1H, m), 7.2-7.7(11H, m)

[0675] MS m/z: 434 (M+H)

[0676] (6)3-Butoxy-4′-[(2R)-2-[[(2R)-2-hydroxy-2-phenylethyl]-amino]propyl]-1,1′-biphenyl-4-carboxylicAcid Hydrochloride

[0677] NMR (DMSO-d₆, δ): 0.94(3H, t, J=7.4 Hz), 1.12(3H, d, J=6.4 Hz),1.3-1.8(4H, m), 2.6-3.2(5H, m), 4.15(2H, q, J=7.0 Hz), 4.9-5.1(1H, m),6.23(1H, m), 7.2-7.7(11H, m)

[0678] MS m/z: 448 (M+H)

[0679] (7)4′-[(2R)-2-[[(2R)-2-Hydroxy-2-phenylethyl]amino]-propyl]-3-(pentyloxy)-1,1′-biphenyl-4-carboxylicAcid Hydrochloride

[0680] NMR (DMSO-d₆, δ): 0.89(3H, t, J=7.4 Hz), 1.13(3H, d, J=6.4 Hz),1.2-1.8(6H, m), 2.6-3.2(5H, m), 4.14(2H, q, J=7.0 Hz), 4.9-5.1(1H, m),6.23(1H, m), 7.2-7.7(11H, m)

[0681] MS m/z: 462 (M+H)

[0682] (8)3-(Heptyloxy)-4′-[(2R)-2-[[(2R)-2-hydroxy-2-phenylethyl]amino]propyl]-1,1′-biphenyl-4-carboxylicAcid Hydrochloride

[0683] NMR (DMSO-d₆, δ): 0.86(3H, t, J=7.4 Hz), 1.16(3H, d, J=6.4 Hz),1.1-1.8(10H, m), 2.6-3.2(5H, m), 4.14(2H, q, J=7.0 Hz), 4.9-5.1(1H, m),6.23(1H, m), 7.2-7.7(11H, m)

[0684] MS m/z: 490 (M+H)

[0685] (9)4′-[(2R)-2-[[(2R)-2-Hydroxy-2-phenylethyl]amino]-propyl]-3-isobutoxy-1,1′-biphenyl-4-carboxylicAcid Hydrochloride

[0686] NMR (DMSO-d₆, δ): 1.03(6H, t, J=6.2 Hz), 1.16(3H, d, J=6.4 Hz),1.8-2.2(1H, m), 2.6-3.2(5H, m), 3.93(2H, d, J=6.2 Hz), 4.9-5.1(1H, m),6.23(1H, m), 7.2-7.7(11H, m)

[0687] MS m/z: 448 (M+H)

[0688] (10)3-(Allyloxy)-4′-[(2R)-2-[[(2R)-2-hydroxy-2-phenylethyl]amino]propyl]-1,1′-biphenyl-4-carboxylicAcid Hydrochloride

[0689] NMR (DMSO-d₆, δ): 1.16(3H, d, J=6.4 Hz), 2.6-3.2(5H, m), 4.77(2H,m), 4.9-5.1(1H, m), 5.27(1H, dd, J=1.8, 10.6 Hz), 5.40(1H, dd, J=1.8,17.2 Hz), 5.9-6.2(1H, m), 6.23(1H, m), 7.2-7.7(11H, m)

[0690] MS m/z: 432 (M+H)

[0691] (11)4′-[(2R)-2-[[(2R)-2-Hydroxy-2-phenylethyl]amino]-propyl]-3-[(2-methyl-2-propenyl)oxy]-1,1′-biphenyl-4-carboxylicAcid Hydrochloride

[0692] NMR (DMSO-d₆, δ): 1.16(3H, d, J=6.4 Hz), 1.69(3H, s), 2.6-3.2(5H,m), 4.77(2H, m), 4.65(2H, s), 4.9-5.1(1H, m), 4.9-5.2(2H, m), 6.23(1H,m), 7.2-7.7(11H, m)

[0693] MS m/z: 446 (M+H)

[0694] (12)3-(2-Fluoroethoxy)-4′-[(2R)-2-[[(2R)-2-hydroxy-2-phenylethyl]amino]propyl]-1,1′-biphenyl-4-carboxylicAcid Hydrochloride

[0695] NMR (DMSO-d₆, δ): 1.16(3H, d, J=6.4 Hz), 2.6-3.2(5H, m),4.3-4.8(4H, m), 4.9-5.1(1H, m), 6.23(1H, m), 7.2-7.7(11H, m)

[0696] MS m/z: 438 (M+H)

[0697] (13)3-(2,2-Difluoroethoxy)-4′-[(2R)-2-[[(2R)-2-hydroxy-2-phenylethyl]amino]propyl]-1,1′-biphenyl-4-carboxylicAcid Hydrochloride

[0698] NMR (DMSO-d₆, δ): 1.13(3H, d, J=6.4 Hz), 2.6-3.2(5H, m),4.3-4.7(2H, m), 4.9-5.1(1H, m), 6.0-6.5(2H, m), 7.2-7.7(11H, m)

[0699] MS m/z: 456 (M+H)

[0700] (14)4′-[(2R)-2-[[(2R)-2-Hydroxy-2-phenylethyl]amino]-propyl]-3-(2,2,2-trifluoroethoxy)-1,1′-biphenyl-4-carboxylicAcid Hydrochloride

[0701] NMR (DMSO-d₆, δ): 1.13(3H, d, J=6.4 Hz), 2.6-3.2(5H, m),4.7-5.1(3H, m), 6.24(1H, m), 7.2-7.7(11H, m)

[0702] MS m/z: 472 (M−H)

[0703] (15)3-(2-Hydroxyethoxy)-4′-[(2R)-2-[[(2R)-2-hydroxy-2-phenylethyl]amino]propyl]-1,1′-biphenyl-4-carboxylicAcid Hydrochloride

[0704] NMR (DMSO-d₆, δ): 1.13(3H, d, J=6.4 Hz), 2.6-3.2(5H, m), 3.8(2H,m), 4.15(2H, m), 4.9-5.1(1H, m), 6.24(1H, m), 7.2-7.7(11H, m)

[0705] MS m/z: 434 (M−H)

[0706] (16)4′-[(2R)-2-[[(2R)-2-Hydroxy-2-phenylethyl]amino]-propyl]-3-(2-methoxyethoxy)-1,1′-biphenyl-4-carboxylicAcid Hydrochloride

[0707] NMR (DMSO-d₆, δ): 1.12(3H, d, J=6.4 Hz), 2.6-3.2(5H, m), 3.33(3H,s), 3.70(2H, m), 4.29(2H, m), 4.9-5.1(1H, m), 6.22(1H, m), 7.2-7.7(11H,m)

[0708] MS m/z: 450 (M+H)

[0709] (17)3-(3-Fluoropropoxy)-4′-[(2R)-2-[[(2R)-2-hydroxy-2-phenylethyl]amino]propyl]-1,1′-biphenyl-4-carboxylicAcid Hydrochloride

[0710] NMR (DMSO-d₆, δ): 1.13(3H, d, J=6.4 Hz), 2.0-2.4(2H, m),2.6-3.2(5H, m), 4.25(2H, t, J=6.0 Hz), 4.56(1H, t, J=5.8 Hz), 4.83(1H,t, J=6.0 Hz), 4.9-5.1(1H, m), 6.24(1H, m), 7.2-7.7(11H, m)

[0711] MS m/z: 452 (M+H)

[0712] (18)4′-[(2R)-2-[[(2R)-2-Hydroxy-2-phenylethyl]amino]-propyl]-3-(3,3,3-trifluoropropoxy)-1,1′-biphenyl-4-carboxylicAcid Hydrochloride

[0713] NMR (DMSO-d₆, δ): 1.13(3H, d, J=6.4 Hz), 2.6-3.2(7H, m), 4.39(2H,t, J=6.0 Hz), 4.9-5.1(1H, m), 6.24(1H, m), 7.2-7.7(11H, m)

[0714] MS m/z: 488 (M+H)

[0715] (19)3-(Cyclopropyloxy)-4′-[(2R)-2-[[(2R)-2-hydroxy-2-phenylethyl]amino]propyl]-1,1′-biphenyl-4-carboxylicAcid Hydrochloride

[0716] NMR (DMSO-d₆, δ): 1.13(3H, d, J=6.4 Hz), 2.6-3.2(5H, m),4.9-5.1(2H, m), 6.24(1H, m), 7.2-7.7(11H, m)

[0717] MS m/z: 432 (M+H)

[0718] (20)3-(Cyclobutyloxy)-4′-[(2R)-2-[[(2R)-2-hydroxy-2-phenylethyl]amino]propyl]-1,1′-biphenyl-4-carboxylicAcid Hydrochloride

[0719] NMR (DMSO-d₆, δ): 1.13(3H, d, J=6.4 Hz), 1.2-2.4(6H, m),2.6-3.2(5H, m), 4.9-5.1(2H, m), 6.24(1H, m), 7.2-7.7(11H, m)

[0720] MS m/z: 446 (M+H)

[0721] (21)3-(Cyclopentyloxy)-4′-[(2R)-2-[[(2R)-2-hydroxy-2-phenylethyl]amino]propyl]-1,1′-biphenyl-4-carboxylicAcid Hydrochloride

[0722] NMR (DMSO-d₆, δ): 1.13(3H, d, J=6.4 Hz), 1.2-2.0(8H, m),2.6-3.2(5H, m), 4.9-5.1(2H, m), 6.24(1H, m), 7.2-7.7(11H, m)

[0723] MS m/z: 460 (M+H)

[0724] (22)3-(Cyclopropylmethoxy)-4′-[(2R)-2-[[(2R)-2-hydroxy-2-phenylethyl]amino]propyl]-1,1¹-biphenyl-4-carboxylicAcid Hydrochloride

[0725] NMR (DMSO-d₆, δ): 0.2-0.7(2H, m), 0.9-1.3(6H, m), 2.6-3.2(5H, m),4.03(2H, d, J=6.6 Hz), 4.9-5.1(1H, m), 6.24(1H, m), 7.2-7.7(11H, m)

[0726] MS m/z: 446 (M+H)

[0727] (23)3-(Cyclohexylmethoxy)-4′-[(2R)-2-[[(2R)-2-hydroxy-2-phenylethyl]amino]propyl]-1,1′-biphenyl-4-carboxylicAcid Hydrochloride

[0728] NMR (DMSO-d₆, δ): 1.0-1.9(14H, m), 2.6-3.2(5H, m), 3.93(2H, d,J=6.6 Hz), 4.9-5.1(1H, m), 6.24(1H, m), 7.2-7.7(11H, m)

[0729] MS m/z: 488 (M+H)

[0730] (24)4′-[2-[[(2R)-2-Phenyl-2-hydroxyethyl]amino]ethyl]-1,1′-biphenyl-4-nitrile

[0731] MS m/z: 457 (M+H)

[0732] (25)4′-[(2R)-2-[[(2R)-2-Hydroxy-2-phenylethyl]amino]-propyl]-3-phenoxy-1,1′-biphenyl-4-carboxylicAcid Hydrochloride

[0733] NMR (DMSO-d₆, δ): 1.13(3H, d, J=6.4 Hz), 2.6-3.2(5H, m),4.9-5.1(1H, m), 6.24(1H, m), 6.8-7.9(16H, m)

[0734] MS m/z: 468 (M+H)

[0735] (26)4′-[2-[[(2R)-2-Hydroxy-2-phenylethyl]amino]ethyl]-3-methoxy-1,1′-biphenyl-4-carboxylicAcid Hydrochloride

[0736] NMR (DMSO-d₆, δ): 2.8-3.3(6H, m), 4.9-5.1(1H, m), 6.22(1H, m),7.2-7.8(12H, m)

[0737] MS m/z: 392(M+H)

[0738] (27)3-Ethoxy-4′-[2-[[(2R)-2-hydroxy-2-phenylethyl]amino]-ethyl]-1,1′-biphenyl-4-carboxylicAcid Hydrochloride

[0739] NMR (DMSO-d₆, δ): 1.35(3H, t, J=6.8 Hz), 2.8-3.3(6H, m), 4.20(2H,q, J=6.8 Hz), 4.9-5.1(1H, m), 6.22(1H, m), 7.2-7.8(12H, m)

[0740] MS m/z: 406 (M+H)

[0741] (28)4′-[2-[[(2R)-2-Hydroxy-2-phenylethyl]amino]ethyl]-3-propoxy-1,1′-biphenyl-4-carboxylicAcid Hydrochloride

[0742] NMR (DMSO-d₆, δ): 1.01(3H, t, J=6.8 Hz), 1.6-1.9(2H, m),2.9-3.4(6H, m), 4.11(2H, q, J=6.8 Hz), 4.9-5.1(1H, m), 6.22(1H, m),7.2-7.8(12H, m)

[0743] MS m/z: 420 (M+H)

[0744] (29)4′-[2-[[(2R)-2-Hydroxy-2-phenylethyl]amino]ethyl]-3-isopropoxy-1,1′-biphenyl-4-carboxylicAcid Hydrochloride

[0745] NMR (DMSO-d₆, δ): 1.31(6H, t, J=6.8 Hz), 2.9-3.4(6H, m),4.7-4.9(1H, m), 4.9-5.1 (1H, m), 6.22(1H, m), 7.2-7.8(12H, m)

[0746] MS m/z: 420 (M+H)

[0747] (30)4′-[2-[[(2R)-2-Hydroxy-2-phenylethyl]amino]ethyl]-3-isobutoxy-1,1′-biphenyl-4-carboxylicAcid Hydrochloride

[0748] NMR (DMSO-d₆, δ): 1.02(6H, t, J=6.8 Hz), 1.9-2.1(1H, m),2.9-3.4(6H, m), 3.92(2H, d, J=6.8 Hz), 4.9-5.1(1H, m), 6.22(1H, m),7.2-7.8(12H, m)

[0749] MS m/z: 434 (M+H)

[0750] (31)3-(Allyloxy)-4′-[2-[[(2R)-2-hydroxy-2-phenylethyl]-amino]ethyl]-1,1′-biphenyl-4-carboxylicAcid Hydrochloride

[0751] NMR (DMSO-d₆, δ): 2.9-3.4(6H, m), 3.92(2H, d, J=6.8 Hz), 4.72(2H,m), 5.2-5.7(2H, m), 4.9-5.1(1H, m), 6.0-6.2(1H, m), 6.22(1H, m),7.2-7.8(12H, m)

[0752] MS m/z: 418(M+H)

[0753] (32)3-(2-Fluoroethoxy)-4′-[2-[[(2R)-2-hydroxy-2-phenylethyl]amino]ethyl]-1,1′-biphenyl-4-carboxylicAcid Hydrochloride

[0754] NMR (DMSO-d₆, δ): 2.9-3.4(6H, m), 4.3-4.7(3H, m), 4.8-4.9(1H, m),4.9-5.1(1H, m), 6.22(1H, m), 7.2-7.8(12H, m)

[0755] MS m/z: 424 (M+H)

[0756] (33)3-(3-Fluoropropoxy)-4′-[2-[[(2R)-2-hydroxy-2-phenylethyl]amino]ethyl]-1,1′-biphenyl-4-carboxylicAcid Hydrochloride

[0757] NMR (DMSO-d₆, δ): 1.9-2.3(2H, m), 2.9-3.4(6H, m), 4.25(2H, t,J=6.0 Hz), 4.56(1H, t, J=5.9 Hz), 4.80(1H, t, J=5.8 Hz), 4.9-5.1(1H, m),6.22(1H, m), 7.2-7.8(12H, m)

[0758] MS m/z: 438 (M+H)

[0759] (34)3-(Cyclopropyloxy)-4′-[2-[[(2R)-2-hydroxy-2-phenylethyl]amino]ethyl]-1,1′-biphenyl-4-carboxylicAcid Hydrochloride

[0760] NMR (DMSO-d₆, δ): 2.9-3.4(6H, m), 4.9-5.1(1H, m), 6.22(1H, m),7.2-7.8(12H, m)

[0761] MS m/z: 392 (M+H)

[0762] (35)3-(Cyclohexyloxy)-4′-[2-[[(2R)-2-hydroxy-2-phenylethyl]amino]ethyl]-1,1′-biphenyl-4-carboxylicAcid Hydrochloride

[0763] NMR (DMSO-d₆, δ): 1.2-2.0(10H, m), 2.9-3.4(6H, m), 4.64(1H, m),4.9-5.1(1H, m), 6.22(1H, m), 7.2-7.8(12H, m)

[0764] MS m/z: 460 (M+H)

[0765] (36)4′-[2-[[(2R)-2-Hydroxy-2-phenylethyl]amino]ethyl]-3-phenoxy-1,1′-biphenyl-4-carboxylicAcid Hydrochloride

[0766] NMR (DMSO-d₆, δ): 2.9-3.4(6H, m), 4.9-5.1(1H, m), 6.22(1H, m),6.9-8.0(17H, m)

[0767] MS m/z: 454 (M+H)

[0768] (37)3-(Benzyloxy)-4′-[2-[[(2R)-2-hydroxy-2-phenylethyl]amino]ethyl]-1,1′-biphenyl-4-carboxylicAcid Hydrochloride

[0769] NMR (DMSO-d₆, δ): 2.9-3.4(6H, m), 4.9-5.1(1H, m), 5.33(2H, m),6.22(1H, m), 7.2-7.8(17H, m)

[0770] MS m/z: 468 (M+H)

[0771] (38)4′-[2-[[(2R)-2-Hydroxy-2-phenylethyl]amino]ethyl]-3-(2,2,2-trifluoroethoxy)-1,1′-biphenyl-4-carboxylicAcid Hydrochloride

[0772] NMR (DMSO-d₆, δ): 2.9-3.4(6H, m), 4.3-5.1(2H, m), 6.22(1H, m),7.2-7.8(12H, m)

[0773] MS m/z: 460(M+H)

[0774] (39)4′-[2-[[(2R)-2-Hydroxy-2-phenylethyl]amino]ethyl]-2-methyl-1,1′-biphenyl-4-carboxylicAcid Hydrochloride

[0775] NMR (DMSO-d₆, δ): 2.28(3H, s), 2.9-3.4(6H, m), 4.9-5.1(1H, m),5.33(2H, m), 6.22(1H, m), 7.2-7.8(12H, m)

[0776] MS m/z: 476 (M+H)

[0777] (40)4′-[2-[[(2R)-2-(3-Fluorophenyl)-2-hydroxyethyl]-amino]ethyl]-3-propoxy-1,1′-biphenyl-4-carboxylicAcid Hydrochloride

[0778] NMR (DMSO-d₆, δ): 1.01(3H, t, J=7.4 Hz), 1.5-1.9(2H, m),2.9-3.4(6H, m), 4.11(2H, q, J=7.4 Hz), 4.9-5.1(1H, m), 6.22(1H, m),7.1-7.8(11H, m)

[0779] MS m/z: 438 (M+H)

[0780] (41)4′-[(2R)-2-[[(2R)-2-(3-Fluorophenyl)-2-hydroxyethyl]-amino]propyl]-3-propoxy-1,1′-biphenyl-4-carboxylicAcid Hydrochloride

[0781] NMR (DMSO-d₆, δ): 0.99(3H, t, J=7.4 Hz), 1.10(3H, d, J=6.8 Hz),1.5-1.9(2H, m), 2.7-3.4(5H, m), 4.03(2H, q, J=7.4 Hz), 4.9-5.1(1H, m),6.22(1H, m), 7.1-7.8(11H, m)

[0782] MS m/z: 450 (M−H)

[0783] (42)4′-[2-[[(2R)-2-(3-Fluorophenyl)-2-hydroxyethyl]amino]-ethyl]-3-isopropoxy-1,1′-biphenyl-4-carboxylicAcid Hydrochloride

[0784] NMR (DMSO-d₆, δ): 1.31(6H, d, J=6.0 Hz), 2.9-3.4(6H, m), 4.81(1H,m), 4.9-5.1(1H, m), 6.22(1H, m), 7.1-7.8(11H, m)

[0785] MS m/z: 438 (M+H)

[0786] (43)4′-[(2R)-2-[[(2R)-2-(3-fluorophenyl)-2-hydroxyethyl]-amino]propyl]-3-isopropoxy-1,1′-biphenyl-4-carboxylicAcid Hydrochloride

[0787] NMR (DMSO-d₆, δ): 1.10(3H, d, J=6.8 Hz), 1.31(6H, d, J=6.0 Hz),2.7-3.4(5H, m), 4.82(1H, m), 4.9-5.1(1H, m), 6.22(1H, m), 7.1-7.8(11H,m)

[0788] MS m/z: 450 (M−H)

[0789] (44)3-(Cyclohexyloxy)-4′-[(2R)-2-[[(2R)-2-(3-fluorophenyl)-2-hydroxyethyl]amino]propyl]-1,1′-biphenyl-4-carboxylicAcid Hydrochloride

[0790] NMR (DMSO-d₆, δ): 1.13(3H, d, J=6.8 Hz), 1.2-2.0(10H, m),2.7-3.4(5H, m), 4.65(1H, m), 4.9-5.1(1H, m), 6.22(1H, m), 7.1-7.8(11H,m)

[0791] MS m/z: 490 (M−H)

[0792] (45)4′-[2-[[(2R)-2-(4-Chlorophenyl)-2-hydroxyethyl]amino]-ethyl]-3-propoxy-1,1′-biphenyl-4-carboxylicAcid Hydrochloride

[0793] NMR (DMSO-d₆, δ): 1.01(3H, t, J=7.4 Hz), 1.5-1.9(2H, m),2.9-3.4(6H, m), 4.10(2H, q, J=7.4 Hz), 4.9-5.1(1H, m), 6.28(1H, m),7.1-7.8(11H, m)

[0794] MS m/z: 438 (M+H)

[0795] (46)4′-[2-[[(2R)-2-(4-Chlorophenyl)-2-hydroxyethyl]amino]-ethyl]-3-isopropoxy-1,1′-biphenyl-4-carboxylicAcid Hydrochloride

[0796] NMR (DMSO-d₆, δ): 1.29(6H, d, J=6.0 Hz), 2.9-3.4(6H, m), 4.84(1H,m), 4.9-5.1(1H, m), 6.30(1H, m), 7.1-7.8(11H, m)

[0797] MS m/z: 454 (M+H)

[0798] (47)4′-[(2R)-2-[[(2R)-2-(4-Chlorophenyl)-2-hydroxyethyl]-amino]propyl]-3-propoxy-1,1′-biphenyl-4-carboxylicAcid Hydrochloride

[0799] NMR (DMSO-d₆, δ): 1.00(3H, t, J=7.4 Hz), 1.12(3H, d, J=6.8 Hz),1.5-1.9(2H, m), 2.7-3.4(5H, m), 4.03(2H, q, J=7.4 Hz), 4.9-5.1(1H, m),6.32(1H, m), 7.1-7.8(11H, m)

[0800] MS m/z: 468 (M−H)

[0801] (48)4′-[(2R)-2-[[(2R)-2-(4-Chlorophenyl)-2-hydroxyethyl]-amino]propyl]-3-isopropoxy-1,1′-biphenyl-4-carboxylicAcid Hydrochloride

[0802] NMR (DMSO-d₆, δ): 1.09(3H, d, J=6.8 Hz), 1.29(6H, d, J=6.0 Hz),2.7-3.4(5H, m), 4.82(1H, m), 4.9-5.1(1H, m), 6.32(1H, m), 7.1-7.8(11H,m)

[0803] MS m/z: 468 (M−H)

[0804] (49)3-Ethoxy-4′-[(2R)-2-[[(2R)-2-hydroxy-2-(3-pyridyl)ethyl]amino]propyl]-1,1′-biphenyl-4-carboxylicAcid dihydrochloride

[0805] NMR (DMSO-d₆, δ): 1.19(3H, d, J=6.8 Hz), 1.36(3H, t, J=7.0 Hz),2.7-3.4(5H, m), 4.23(2H, q, J=7.0 Hz), 5.1-5.3(1H, m), 6.32(1H, m),7.2-7.9(8H, m), 8.25(1H, d, J=8 Hz), 8.7-8.9(2H, m), 8.94(1H, m),9.20(1H, m)

[0806] MS m/z: 421 (M+H)

[0807] (50)4′-[(2R)-2-[[(2R)-2-Hydroxy-2-(3-pyridyl)ethyl]-amino]propyl]-3-propoxy-1,1′-biphenyl-4-carboxylicAcid Hydrochloride

[0808] NMR (DMSO-d₆, δ): 1.01(3H, t, J=7.4 Hz), 1.19(3H, d, J=6.8 Hz),1.5-1.9(2H, m), 2.7-3.4(5H, m), 4.04(2H, q, J=7.4 Hz), 5.1-5.3(1H, m),6.32(1H, m), 7.2-7.9(8H, m), 8.25(1H, d, J=8 Hz), 8.7-8.9(2H, m),8.94(1H, m), 9.20(1H, m)

[0809] MS m/z: 435 (M+H)

[0810] (51)4′-[(2R)-2-[[(2R)-2-Hydroxy-2-(3-pyridyl)ethyl]-amino]propyl]-3-isobutoxy-1,1′-biphenyl-4-carboxylicAcid dihydrochloride

[0811] NMR (DMSO-d₆, δ): 1.01(6H, t, J=6.8 Hz), 1.17(3H, d, J=6.8 Hz),1.9-2.1(1H, m), 2.7-3.4(5H, m), 3.93(2H, d, J=6.4 Hz), 5.2-5.4(1H, m),7.2-7.9(8H, m), 8.4(1H, d, J=8 Hz), 8.7-8.9(2H, m), 9.09(1H, m),9.42(1H, m)

[0812] MS m/z: 449 (M+H)

[0813] (52)N-[[4′-[(2R)-2-[[(2R)-2-Hydroxy-2-(3-pyridyl)ethyl]-amino]propyl]-1,1′-biphenyl-4-yl]carbonyl]-1phenylmethanesulfonamide dihydrochloride

[0814] MS m/z: 528 (M−H)

[0815] (53)4′-[(2R)-2-[[(2R)-2-(6-Chloro-3-pyridyl)-2-hydroxyethyl]amino]propyl]-3-propoxy-1,1′-biphenyl-4-carboxylicAcid dihydrochloride

[0816] NMR (DMSO-d₆, δ): 1.01(3H, t, J=7.4 Hz), 1.12(3H, d, J=6.8 Hz),1.7-1.9(2H, m), 2.7-3.4(5H, m), 4.11(2H, q, J=7.4 Hz), 4.9-5.3(1H, m),7.2-7.8(10H, m), 8.56(1H, s)

[0817] MS m/z: 469 (M+H)

[0818] (54)4′-[2-[[(2R)-2-Hydroxy-2-(3-pyridyl)ethyl]amino]-ethyl]-3-isopropoxy-1,1′-biphenyl-4-carboxylicAcid dihydrochloride

[0819] NMR (DMSO-d₆, δ): 1.29(6H, d, J=6.0 Hz), 2.9-3.4(6H, m), 4.84(1H,m), 4.9-5.1(1H, m), 7.2-7.5(4H, m), 7.6-7.9(4H, m), 8.2-8.5(1H, m),8.7-8.9(2H, m), 9.0-9.4(2H, m)

[0820] MS m/z: 421 (M+H)

[0821] (55)4′-[2-[[(2R)-2-Hydroxy-2-(3-pyridyl)ethyl]amino]-ethyl]-3-propoxy-1,1′-biphenyl-4-carboxylicAcid dihydrochloride

[0822] NMR (DMSO-d₆, δ): 1.01(3H, t, J=7.4 Hz), 1.5-1.9(2H, m),3.0-3.4(6H, m), 4.11(2H, q, J=7.4 Hz), 5.0-5.3(1H, m), 7.2-7.5(4H, m),7.6-7.9(4H, m), 8.3-8.5(1H, m), 8.7-8.9(2H, m), 9.0-9.4(2H, m)

[0823] MS m/z: 421 (M+H)

[0824] (56)3-(Cyclohexyloxy)-4′-[2-[[(2R)-2-hydroxy-2-(3-pyridyl)ethyl]amino]ethyl]-1,1′-biphenyl-4-carboxylicAcid dihydrochloride

[0825] NMR (DMSO-d₆, δ): 1.0-2.0(10H, m), 2.9-3.4(6H, m), 4.65(1H, m),5.0-5.3(1H, m), 7.2-7.5(4H, m), 7.6-8.0(4H, m), 8.4-8.6(1H, m),8.7-8.9(2H, m), 9.0-9.4(2H, m)

[0826] MS m/z: 461 (M−H)

[0827] (57)4′-[2-[[(2R)-2-(6-Chloro-3-pyridyl)-2-hydroxyethyl]-amino]ethyl]-3-propoxy-1,1′-biphenyl-4-carboxylicAcid dihydrochloride

[0828] NMR (DMSO-d₆, δ): 1.01(3H, t, J=7.4 Hz), 1.6-1.9(2H, m),3.0-3.4(6H, m), 4.11(2H, q, J=7.4 Hz), 5.0-5.3(1H, m), 7.1-7.9(9H, m),8.46(1H, s)

[0829] MS m/z: 453 (M−H)

[0830] (58)3-Butyl-4′-[(2R)-2-[[(2R)-2-hydroxy-2-phenylethyl]-amino]propyl]-1,1′-biphenyl-4-carboxylicAcid Hydrochloride

[0831] NMR (DMSO-d₆, δ): 0.90(3H, t, J=7.4 Hz), 1.0-1.8(9H, m),2.8-3.8(5H, m), 5.0-5.3(1H, m), 6.3-6.4(1H, m), 7.2-7.8(11H, m)

[0832] MS m/z: 432(M+H)

[0833] (59)3-(3-Butenyl)-4′-[(2R)-2-[[(2R)-2-hydroxy-2-phenylethyl]amino]propyl]-1,1′-biphenyl-4-carboxylicAcid Hydrochloride

[0834] MS m/z: 430 (M+H)

[0835] (60)4′-[2-[[(2R)-2-hydroxy-2-phenylethyl]amino]-2-methylpropyl]-3-isopropoxy-1,1′-biphenyl-4-carboxylicAcid Hydrochloride

[0836] MS m/z: 482 (M+H)

[0837] (61)4′-[3-[[(2R)-2-Hydroxy-2-phenylethyl]amino]propyl]-3-isopropoxy-1,1′-biphenyl-4-carboxylicAcid Hydrochloride

[0838] MS m/z: 434 (M+H)

[0839] (62)4′-[2-[[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino]-ethyl]-3-isopropoxy-1,1′-biphenyl-4-carboxylicAcid Hydrochloride

[0840] NMR (DMSO-d₆, δ): 1.31 (6H, d, J=6.0 Hz), 2.8-3.0 (6H, m), 4.79(1H, q, J=6.0 Hz), 4.8-5.0 (1H, m), 6.33 (1H, m), 7.0-7.9 (1H, m)

[0841] MS m/z: 454 (M+H)

[0842] (63) Ethyl4′-[2-[N-(tert-butoxycarbonyl)-N-[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]-1,1′-biphenyl-3-carboxylate

[0843] (+)ESI-MS m/z: 524 (M+H)⁺

[0844] (64) Methyl3′-[2-[N-(tert-butoxycarbonyl)-N-[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]-1,1′-biphenyl-4-carboxylate

[0845] (+)ESI-MS m/z: 510 (M+H)⁺

[0846] (65) Methyl4′-[2-[N-(tert-butoxycarbonyl)-N-[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]-2-fluoro-1,1′-biphenyl-4-carboxylate

[0847] (+)ESI-MS m/z: 550 (M+Na)⁺

[0848] (66) Methyl4′-[2-[N-(tert-butoxycarbonyl)-N-[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]-3-chloro-1,1′-biphenyl-4-carboxylate

[0849] (+)ESI-MS m/z: 566 (M+Na)⁺

[0850] (67) Methyl4′-[2-[N-(tert-butoxycarbonyl)-N-[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]-2′-methoxy-1,1′-biphenyl-4-carboxylate

[0851] (+)ESI-MS m/z: 540 (M+H)⁺

[0852] (68) Methyl4′-[2-[N-(tert-butoxycarbonyl)-N-[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]-2′-chloro-1,1′-biphenyl-4-carboxylate

[0853] (+)ESI-MS m/z: 544 (M+H)⁺

[0854] (69) tert-ButylN-[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]-N-[2-[4′-formyl-3′-(1-piperidinyl)-1,1′-biphenyl-4-yl]ethyl]carbamate

[0855] (+)ESI-MS m/z: 563 (M+H)⁺

[0856] (70) Methyl4′-[3-[N-(tert-butoxycarbonyl)-N-[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]propyl]-1,1′-biphenyl-4-carboxylate

[0857] MS (m/z): 524 (M+H)

[0858] (71) Ethyl4′-[3-[N-(tert-butoxycarbonyl)-N-[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]propyl]-1,1′-biphenyl-3-carboxylate

[0859] MS (m/z): 538 (M+H)

[0860] (72) Methyl4′-[3-[N-(tert-butoxycarbonyl)-N-[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]propyl]-3-fluoro-1,1′-biphenyl-4-carboxylate

[0861] MS (m/z): 542 (M+H)

[0862] (73) Methyl4′-[3-[N-(tert-butoxycarbonyl)-N-[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]propyl]-3-methoxy-1,1′-biphenyl-4-carboxylate

[0863] MS (m/z): 554 (M+H)

[0864] (74) Methyl4′-[3-[N-(tert-butoxycarbonyl)-N-[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]propyl]-3-chloro-1,1′-biphenyl-4-carboxylate

[0865] MS (m/z): 558 (M+H)

[0866] (75) Methyl4′-[3-[N-(tert-butoxycarbonyl)-N-[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]propyl]-3-methyl-1,1′-biphenyl-4-carboxylate

[0867] MS (m/z): 538 (M+H)

[0868] (76) Methyl3′-[3-[N-(tert-butoxycarbonyl)-N-[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]propyl]-1,1′-biphenyl-4-carboxylate

[0869] MS (m/z): 523 (M+H)

[0870] (77) Ethyl3′-[3-[N-(tert-butoxycarbonyl)-N-[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]propyl]-1,1′-biphenyl-3-carboxylate

[0871] MS (m/z): 538 (M+H)

[0872] (78) Methyl4′-[2-[N-(tert-butoxycarbonyl)-N-[(2R)-2-(5-chloro-3-pyridyl)-2-hydroxyethyl]amino]ethyl]-1,1′-biphenyl-4-carboxylate

[0873] MS (m/z): 511 (M+H)

[0874] (79) tert-ButylN-[(2R)-2-(6-chloro-3-pyridyl)-2-hydroxyethyl]-N-[(1R)-2-(4′-formyl-3′-phenoxy-1,1′-biphenyl-4-yl)-1-methylethyl]carbamate

[0875] MS (m/z): 587 (M+H)

[0876] (80) tert-ButylN-[2-(4′-formyl-3′-phenoxy-1,1′-biphenyl-4-yl)ethyl]-N-[(2R)-2-hydroxy-2-(3-pyridyl)ethyl]-carbamate

[0877] MS (m/z): 539 (M+H)

[0878] (81) Methyl[4′-[2-[N-(tert-butoxycarbonyl)-N-[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]-1,1′-biphenyl-4-yl]acetate

[0879] MS (m/z): 524 (M+H)

[0880] (82) Methyl[4′-[2-[N-(tert-butoxycarbonyl)-N-[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]-1,1′-biphenyl-3-yl]acetate

[0881] MS (m/z): 524 (M+H)

[0882] (83) Methyl4-[4-[(2R)-2-[N-(tert-butoxycarbonyl)-N-[(2R)-2-(6-chloro-3-pyridyl)-2-hydroxyethyl]amino]propyl]-phenyl]-1-naphthoate

[0883] MS (m/z): 575 (M+H)

[0884] (84) tert-ButylN-[(1R)-2-[4′-[(benzoylamino)sulfonyl]-1,1¹-biphenyl-4-yl]-1-methylethyl]-N-[(2R)-2-(6-chloro-3-pyridyl)-2-hydroxyethyl]carbamate

[0885] MS (m/z): 650 (M+H)

[0886] (85) tert-ButylN-[2-[4′-formyl-3′-(1-piperidinyl)-1,1′-biphenyl-4-yl]ethyl]-N-[(2R)-2-hydroxy-2-phenylethyl]-carbamate

[0887] MS (m/z): 529 (M+H)

[0888] (86)4′-[2-[[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino]-ethyl]-3-(2-methoxyethoxy)-1,1′-biphenyl-4-carboxylicAcid Hydrochloride

[0889] MS (m/z): 470 (M+H)

[0890] (87)3-(2-Ethoxyethoxy)-4′-[2-[[(2R)-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]-1,1′-biphenyl-4-carboxylicAcid Hydrochloride

[0891] MS (m/z): 484 (M+H)

[0892] (88)4′-[2-[[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino]-ethyl]-3-propyl-1,1′-biphenyl-4-carboxylicAcid Hydrochloride

[0893] MS (m/z): 438 (M+H)

[0894] (89)4′-[2-[[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino]-ethyl]-3-propoxy-1,1′-biphenyl-4-carboxylicAcid Hydrochloride

[0895] MS (m/z): 454 (M+H)

[0896] (90)4′-[2-[[(2R)-2-Hydroxy-2-phenylethyl]amino]ethyl]-3-(2-methoxyethoxy)-1,1′-biphenyl-4-carboxylicAcid Hydrochloride

[0897] NMR (DMSO-d₆, δ): 2.8-3.0 (6H, m), 3.32 (3H, s), 3.70 (2H, m),4.29 (2H, m), 4.8-5.0 (1H, m), 6.33 (1H, m), 7.0-7.9 (12H, m)

[0898] MS m/z: 436 (M+H)

[0899] (91)3-(2-Ethoxyethoxy)-4′-[2-[[(2R)-2-hydroxy-2-phenylethyl]amino]ethyl]-1,1′-biphenyl-4-carboxylicAcid Hydrochloride

[0900] MS m/z: 450 (M+H)

[0901] (92)3-[2-(Dimethylamino)ethoxy]-4′-[2-[[(2R)-2-hydroxy-2-phenylethyl]amino]ethyl]-1,1′-biphenyl-4-carboxylicAcid dihydrochloride

[0902] NMR (DMSO-d₆, δ): 1.12 (3H, d, J=6.5 Hz), 2.8-3.6 (7H, m), 2.88(6H, s), 4.58 (2H, m), 4.8-5.0 (1H, m), 6.33 (1H, m), 7.0-7.9 (12H, m)

[0903] MS m/z: 462 (M+H)

[0904] (93)4′-[2-[[(1S,2R)-2-Hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino]ethyl]-3-isopropoxy-1,1′-biphenyl-4-carboxylicAcid Hydrochloride

[0905] NMR (DMSO-d₆, δ): 0.98 (3H, d, J=6.6 Hz), 1.31 (6H, d, J=6.0 Hz),2.8-3.5 (5H, m), 4.79 (1H, q, J=6.0 Hz), 5.0-5.2 (1H, m), 6.0 (1H, m),6.7-7.9 (11H, m)

[0906] MS m/z: 450 (M+H)

EXAMPLE 33

[0907] To the mixture of4′-[2-[[(2R)-2-phenyl-2-hydroxyethyl]amino]ethyl]-1,1′-biphenyl-4-nitrile(100 mg) in DMF (N,N-dimethylformamide) (10 ml) were added sodium azide(30 mg) and ammonium chloride (30 mg), and stirred at 120° C. for 12hours. The resulting mixture was poured into a mixture of ethyl acetateand water, and the organic layer was washed with brine. After thesolvent was evaporated under pressure, the residue was purified bycolumn chromatography on silica gel to give the corresponding tetrazole.The obtained tetrazole was diluted with 6N hydrogen chloride in1,4-dioxane (10 ml) and the mixture was allowed to keep at the roomtemperature for 4 hours. The mixture was evaporated under reducedpressure and the obtained solid was washed with ether to give(1R)-2-[[(1R)-1-methyl-2-[4¹-(1H-tetrazol-5-yl)-1,1′-biphenyl-4-yl]ethyl]amino]-1-phenylethanolhydrochloride (25 mg).

[0908] NMR (DMSO-d₆, δ): 1.14(3H, d, J=6.4 Hz), 2.6-3.2(5H, m), 3.93(2H,d, J=6.6 Hz), 4.9-5.1(1H, m), 6.24(1H, m), 7.2-7.5(7H, m), 7.77(2H, d,J=8.0 Hz), 7.94(2H, d, J=8.0 Hz), 8.15(2H, d, J=8.0 Hz)

[0909] MS m/z: 400 (M+H)

EXAMPLE 34

[0910] The following compounds were obtained according to a similarmanner to that of Example 30.

[0911] (1)4′-[3-[N-(tert-Butoxycarbonyl)-N-[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]propyl]-1,1′-biphenyl-4-carboxylicAcid

[0912] MS (m/z): 510 (M+H)

[0913] (2)4′-[3-[N-(tert-Butoxycarbonyl)-N-[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]propyl]-1,1′-biphenyl-3-carboxylicAcid

[0914] MS (m/z): 510 (M+H)

[0915] (3)4′-[3-[N-(tert-Butoxycarbonyl)-N-[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]propyl]-3-fluoro-1,1′-biphenyl-4-carboxylicAcid

[0916] MS (m/z): 528 (M+H)

[0917] (4)4′-[3-[N-(tert-Butoxycarbonyl)-N-[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]propyl]-3-methoxy-1,1′-biphenyl-4-carboxylicAcid

[0918] MS (m/z): 540 (M+H)

[0919] (5)4′-[3-[N-(tert-Butoxycarbonyl)-N-[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]propyl]-3-chloro-1,1′-biphenyl-4-carboxylicAcid

[0920] MS (m/z): 544 (M+H)

[0921] (6)4′-[3-[N-(tert-Butoxycarbonyl)-N-[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]propyl]-3-methyl-1,1′-biphenyl-4-carboxylicAcid

[0922] MS (m/z): 524 (M+H)

[0923] (7)3′-[3-[N-(tert-Butoxycarbonyl)-N-[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]propyl]-1,1′-biphenyl-4-carboxylicAcid

[0924] MS (m/z): 523 (M+H)

[0925] (8)3′-[3-[N-(tert-Butoxycarbonyl)-N-[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]propyl]-1,1′-biphenyl-3-carboxylicAcid

[0926] MS (m/z): 510 (M+H)

[0927] (9)[4′-[(2R)-2-[N-(tert-Butoxycarbonyl)-N-[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]propyl]-1,1′-biphenyl-4-yl]aceticAcid

[0928] MS (m/z): 524 (M+H)

[0929] (10)4′-[2-[N-(tert-Butoxycarbonyl)-N-[(2R)-2-(5-chloro-3-pyridyl)-2-hydroxyethyl]amino]ethyl]-1,1′-biphenyl-4-carboxylicAcid

[0930] MS (m/z): 497 (M+H)

[0931] (11)[4′-[2-[N-(tert-Butoxycarbonyl)-N-[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]-1,1′-biphenyl-4-yl]aceticAcid

[0932] MS (m/z): 510 (M+H)

[0933] (12)4-[4-[N-(2R)-2-[N-(tert-Butoxycarbonyl)-N-[(2R)-2-(6-chloro-3-pyridyl)-2-hydroxyethyl]amino]propyl]phenyl]-1-naphthoicAcid

[0934] MS (m/z): 561 (M+H)

EXAMPLE 35

[0935] The following compounds were obtained according to a similarmanner to that of Example 27.

[0936] (1)4′-[3-[[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino]-propyl]-1,1′-biphenyl-4-carboxylicAcid Hydrochloride

[0937] NMR (DMSO-d₆, δ): 1.70-2.10(2H, m), 2.60-3.40(6H, m),4.90-5.10(1H, m), 7.40-7.60(6H, m), 7.70-7.90(4H, m), 8.10(1H, d, J=8Hz)

[0938] MS (m/z): 410 (M+H)

[0939] (2)4′-[3-[[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]-amino]propyl]-1,1′-biphenyl-3-carboxylicAcid Hydrochloride

[0940] NMR (DMSO-d₆, δ): 1.80-2.10(2H, m), 2.60-3.40(6H, m),4.90-5.10(1H, m), 7.30-7.60(9H, m), 7.80-7.90(1H, m), 8.10(1H, s)

[0941] MS (m/z): 410 (M+H)

[0942] (3)4′-[3-[[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino]-propyl]-3-fluoro-1,1′-biphenyl-4-carboxylicAcid Hydrochloride

[0943] NMR (DMSO-d₆, δ): 1.80-2.10(2H, m), 2.60-3.40(6H, m),4.90-5.10(1H, m), 7.30-7.80(10H, m), 8.00(1H, t, J=8 Hz)

[0944] MS (m/z): 428 (M+H)

[0945] (4)4′-[3-[[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino]-propyl]-3-methoxy-1,1′-biphenyl-4-carboxylicAcid Hydrochloride

[0946] NMR (DMSO-d₆, δ): 1.80-2.10(2H, m), 2.60-3.40(6H, m), 4.00(3H,s), 4.90-5.10(1H, m), 7.30-7.50(8H, m), 7.70-7.80(3H, m)

[0947] MS (m/z): 440 (M+H)

[0948] (5)3-Chloro-4′-[3-[[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]propyl]-1,1′-biphenyl-4-carboxylicAcid Hydrochloride

[0949] NMR (DMSO-d₆, δ): 1.80-2.10(2H, m), 2.60-3.40(6H, m),4.90-5.10(1H, m), 7.30-7.60(6H, m), 7.70-7.90(5H, m)

[0950] MS (m/z): 444 (M+H)

[0951] (6)4′-[3-[[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino]-propyl]-3-methyl-1,1¹-biphenyl-4-carboxylicAcid Hydrochloride

[0952] NMR (DMSO-d₆, δ): 1.80-2.10(2H, m), 2.60(3H, s), 2.60-3.40(6H,m), 4.90-5.10(1H, m),7.30-7.60(10H, m), 7.90(1H, s)

[0953] MS (m/z): 424 (M+H)

[0954] (7)3′-[3-[[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino)-propyl]-1,1′-biphenyl-4-carboxylicAcid Hydrochloride

[0955] NMR (DMSO-d₆, δ): 1.80-2.10(2H, m), 2.60-3.40(6H, m),4.90-5.10(1H, m), 7.30-7.60(8H, m), 7.80(2H, d, J=8 Hz), 8.10(2H, d, J=8Hz)

[0956] MS (m/z): 410 (M+H)

[0957] (8)3′-[3-[[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino]-propyl]-1,1¹-biphenyl-3-carboxylicAcid Hydrochloride

[0958] NMR (DMSO-d₆, δ): 1.80-2.10(2H, m), 2.60-3.40(6H, m),4.90-5.10(1H, m), 7.30-7.60(9H, m), 7.80-7.90(2H, m), 8.20(1H, s)

[0959] MS (m/z): 410 (M+H)

[0960] (9)[4′-[(2R)-2-[[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]-amino]propyl]-1,1′-biphenyl-4-yl]aceticAcid Hydrochloride

[0961] NMR (DMSO-d₆, δ): 1.05(3H, d, J=6 Hz), 2.80-3.60(7H, m),5.00-5.15(1H, m), 7.20-7.70(12H, m)

[0962] MS (m/z): 424 (M+H)

[0963] (10)4′-[2-[[(2R)-2-(5-Chloro-3-pyridyl)-2-hydroxyethyl]-amino]ethyl]-1,1′-biphenyl-4-carboxylicAcid dihydrochloride

[0964] NMR (DMSO-d₆, δ): 3.10-3.40(6H, m), 5.00-5.10(1H, m),7.40-8.10(9H, m), 7.70-7.80(2H, m)

[0965] MS (m/z): 397 (M+H)

[0966] (11)4′-[(2R)-2-[[(2R)-2-Hydroxy-2-(3-pyridyl)ethyl]-amino]propyl]-3-phenoxy-1,1′-biphenyl-4-carboxylicAcid dihydrochloride

[0967] NMR (DMSO-d₆, δ): 1.13(3H, d, J=6 Hz), 2.70-2.80(1H, m),2.80-3.60(4H, m), 5.30-5.40(1H, m),6.90-7.60(7H, m), 7.90-8.00(2H, m),8.50-8.60(1H, m), 8.80-8.90(2H, m)

[0968] MS (m/z): 469 (M+H)

[0969] (12)4′-[2-[[(2R)-2-Hydroxy-2-(3-pyridyl)ethyl]amino]-ethyl]-3-phenoxy-1,1′-biphenyl-4-carboxylicAcid dihydrochloride

[0970] NMR (DMSO-d₆, δ): 3.00-3.50(6H, m), 5.20-5.30(1H, m),7.00-7.70(7H, m), 7.90-8.00(2H, m), 8.40-8.50(1H, m), 8.80-8.90(2H, m)

[0971] MS (m/z): 455 (M+H)

[0972] (13)[4′-[2-[[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino]-ethyl]-1,1′-biphenyl-4-yl]aceticAcid Hydrochloride

[0973] NMR (DMSO-d₆, δ): 2.90-3.40(6H, m), 3.62(2H, s), 4.90-5.10(1H,m), 7.30-7.70(12H, m)

[0974] MS (m/z): 410 (M+H)

[0975] (14)N-Benzoyl-4′-[(2R)-2-[[(2R)-2-hydroxy-2-(3-pyridyl)ethyl]amino]propyl]-1,1′-biphenyl-4-sulfonamidedihydrochloride

[0976] NMR (DMSO-d₆, δ): 1.01(3H, d, J=6 Hz), 2.60-3.60(5H, m),5.00-5.15(1H, m), 7.20-8.10(13H, m), 8.30-8.40(1H, m), 8.70-8.80(2H, m)

[0977] MS (m/z): 516 (M+H)

[0978] (15)4′-[2-[[(2R)-2-Hydroxy-2-phenylethyl]amino]ethyl]-3-(1-piperidinyl)-1,1′-biphenyl-4-carboxylicAcid dihydrochloride

[0979] NMR (DMSO-d₆, δ): 1.50-1.80(6H, d, m), 3.00-3.40(10H, m),5.00-5.10(1H, m), 7.20-7.50(7H, m), 7.70-7.80(3H, m), 8.10-8.20(2H, m)

[0980] MS (m/z): 445 (M+H)

EXAMPLE 36

[0981] The following compounds were obtained according to a similarmanner to that of Example 21.

[0982] (1) Methyl4′-[2-[[(2R)-2-(6-chloro-3-pyridyl)-2-hydroxyethyl]amino]ethyl]-1,1′-biphenyl-4-carboxylate

[0983] MS (m/z): 410 (M+H)

[0984] (2) Methyl[4′-[(2R)-2-[[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]propyl]-1,1′-biphenyl-4-yl]acetate

[0985] MS (m/z): 438 (M+H)

[0986] (3) Ethyl5-[4-[(2R)-2-[[(2R)-2-(6-chloro-3-pyridyl)-2-hydroxyethyl]amino]propyl]phenyl]-1-naphthoate

[0987] MS (m/z): 489 (M+H)

[0988] (4) Methyl4′-[2-[[(2R)-2-(4-chlorophenyl)-2-hydroxyethyl]amino]ethyl]-1,1′-biphenyl-4-carboxylate

[0989] MS (m/z): 410 (M+H)

[0990] (5) Ethyl6-[4-[2-[N-benzyl-N-[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]phenyl]nicotinate

[0991] (+)ESI-MS m/z: 515 (M+H)⁺

[0992] (6) Methyl4′-[2-[N-benzyl-N-[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]-2,6-dimethyl-1,1′-biphenyl-4-carboxylate

[0993] (+)ESI-MS m/z: 528(M+H)⁺

EXAMPLE 37

[0994] Under nitrogen to a solution of methyl4′-[2-[[(2R)-2-(6-chloro-3-pyridyl)-2-hydroxyethyl]amino]ethyl]-1,1′-biphenyl-4-carboxylate(110 mg) in tetrahydrofran (10 ml) was added 1M methylzinc chloride intetrahydrofran (0.8 ml) and tetrakis(triphenylphosphine)palladium (15.5mg) at room temperature. The mixture was stirred at 80° C. for 24 hours,and then poured into an aqueous solution (60 ml) ofethylenediaminetetraacetic acid (1 g). The resulting mixture wasneutralized with saturated aqueous sodium bicarbonate and extracted withethyl acetate. The organic layer was washed with brine, dried overanhydrous magnesium sulfate and evaporated under reduced pressure. Theresidue was purified by column chromatography on silica gel(chloroform:methanol=100:1) to give methyl4′-[2-[(2R)-2-hydroxy-2-(6-methyl-3-pyridyl)ethyl]amino]ethyl]-1,1′-biphenyl-4-carboxylate(41 mg) as a colorless oil.

[0995] MS (m/z): 391 (M+H)

EXAMPLE 38

[0996] The following compounds were obtained by alkaline hydrolysis ofeach ester thereof in a conventional manner.

[0997] (1) Sodium4′-[2-[[(2R)-2-hydroxy-2-(6-methyl-3-pyridyl)ethyl]amino]ethyl]-1,1′-biphenyl-4-carboxylate

[0998] NMR (DMSO-d₆, δ): 2.50(3H, s), 2.60-2.90(6H, m), 4.60-4.70(1H,m), 7.10-7.40(3H, m), 7.50-7.70(5H, m), 7.90(1H, d, J=8 Hz), 8.40(1H, s)

[0999] (2) Sodium4′-[2-[[(2R)-2-(6-chloro-3-pyridyl)-2-hydroxyethyl]amino]ethyl]-1,1′-biphenyl-4-carboxylate

[1000] NMR (DMSO-d₆, δ): 2.80-3.80(6H, m), 4.90(1H, t, J=6 Hz),7.10-7.90(8H, m), 7.98(2H, d, J=8 Hz), 8.30(1H, d, J=2 Hz)

[1001] MS (m/z): 397 (M+H)

[1002] (3) Sodium4′-[2-[[(2R)-2-(4-chlorophenyl)-2-hydroxyethyl]amino]ethyl]-1,1′-biphenyl-4-carboxylate

[1003] NMR (DMSO-d₆, δ): 2.70-3.50(6H, m), 4.50-4.60(1H, m),7.10-7.60(8H, m), 7.94(2H, d, J=8 Hz)

[1004] MS (m/z): 396 (M+H)

EXAMPLE 39

[1005] The following compounds were obtained according to a similarmanner to that of Preparation 29.

[1006] (1) Methyl[4′-[(2R)-2-[N-(tert-butoxycarbonyl)-N-[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]propyl]-1,1′-biphenyl-4-yl]acetate

[1007] MS (m/z): 538 (M+H)

[1008] (2) Ethyl5-[4-[(2R)-2-[N-(tert-butoxycarbonyl)-N-[(2R)-2-(6-chloro-3-pyridyl)-2-hydroxyethyl]amino]propyl]-phenyl]-1-naphthoate

[1009] MS (m/z): 589 (M+H)

EXAMPLE 40

[1010] The following compounds were obtained according to a similarmanner to that of Example 18.

[1011] (1)[4′-[2-[[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino]-ethyl]-1,1′-biphenyl-3-yl]aceticAcid Hydrochloride

[1012] NMR (DMSO-d₆, δ): 2.80-3.40(6H, m), 3.65(2H, s), 4.90-5.10(1H,m), 7.20-7.70(12H, m)

[1013] MS (m/z): 408 (M−H)

[1014] (2)4′-[2-[[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino]-ethyl]-1,1′-biphenyl-3-carboxylicAcid Hydrochloride

[1015] NMR (DMSO-d₆, δ): 3.01-3.29(6H, m), 4.97-5.02(1H, m), 6.34(1H,br), 6.90(1H, m), 7.71-7.48(9H, m), 7.89-7.95(2H, m),8.18(1H, d, J=1.5Hz), 8.96(1H,br)

[1016] (−)ESI-MS m/z: 394 (M−HCl−H)⁻

[1017] (3)3-[2-[[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino]-ethyl]-6H-benzo[c]chromene-8-carboxylicAcid Hydrochloride

[1018] NMR (DMSO-d₆, δ): 3.00-3.28(6H, m), 4.96-5.01(1H, m), 5.20(2H,s), 6.34(1H, br), 6.94-7.03(2H, m), 7.34-7.47(4H, m), 7.86-7.94(4H, m),8.94(1H, br)

[1019] (−)ESI-MS m/z: 422 (M−HCl−H)⁻

[1020] (4)2-[2-[[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino]-ethyl]-6H-benzo[c]chromene-8-carboxylicAcid Hydrochloride

[1021] NMR (DMSO-d₆, δ): 3.00-3.26(6H, m), 5.03-5.07(1H, m), 5.19(2H,s), 6.38(1H, br), 6.99(1H, d, J=8.2 Hz), 7.20-7.25(2H, m), 7.35-7.48(4H,m), 7.85-7.98(4H, m), 9.10(1H, br)

[1022] (−)ESI-MS m/z: 422 (M−HCl−H)⁻

[1023] (5)6-[4-[2-[[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]-amino]ethyl]phenyl]nicotinicAcid Hydrochloride

[1024] NMR (DMSO-d₆, δ): 3.08-3.24(6H, m), 5.00-5.07(1H, br),7.34-7.47(6H, m), 8.09-8.17 (3H, m), 8.31-8.38(1H, m), 8.98(1H, br),9.12-9.16(1H, m), 9.30(1H, br)

[1025] (−)ESI-MS m/z: 395 (M−HCl−H)⁻

[1026] (6)3′-[2-[[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino]-ethyl]-1,1′-biphenyl-4-carboxylicAcid Hydrochloride

[1027] NMR (DMSO-d₆, δ): 3.01-3.28(6H, m), 4.97-5.02(1H, m), 6.34(1H,br), 7.34-7.48(6H, m), 7.62-7.65(2H, m), 7.78-7.83(2H, m), 8.01-8.05(2H,m), 8.96(1H, br)

[1028] (−)ESI-MS m/z: 394 (M−HCl−H)⁻

[1029] (7)4¹-[2-[[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino]-ethyl]-2-fluoro-1,1′-biphenyl-4-carboxylicAcid Hydrochloride

[1030] NMR (DMSO-d₆, δ): 3.01-3.28(6H, m), 5.02-5.05(1H, m), 6.38(1H,br), 7.37-7.87(11H, m), 9.10(1H, br)

[1031] (−)ESI-MS m/z: 412 (M−HCl−H)⁻

[1032] (8)4′-[2-[[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino]-ethyl]-2,6-dimethyl-1,1′-biphenyl-4-carboxylicAcid Hydrochloride

[1033] NMR (DMSO-d₆, δ): 2.00(6H, m), 3.06-3.11(6H, m),4.98-5.04(1H, m),6.36-6.85(1H, br), 7.11-7.15(2H, m),7.35-7.49(6H, m), 7.70-7.72(2H, m),9.06(1H, br)

[1034] (−)ESI-MS m/z: 422 (M−HCl−H)⁻

[1035] (9)3-Chloro-4′-[2-[[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]-1,1′-biphenyl-4-carboxylicAcid Hydrochloride

[1036] NMR (DMSO-d₆, δ): 3.01-3.28(6H, m), 5.00-5.04(1H, m), 6.36(1H,br), 7.35-7.47(6H, m), 7.70-7.91(5H, m), 9.07(1H, br)

[1037] (−)ESI-MS m/z: 428 (M−HCl−H)⁻

[1038] (10)4′-[2-[[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino]-ethyl]-2′-methoxy-1,1′-biphenyl-4-carboxylicAcid Hydrochloride

[1039] NMR (DMSO-d₆, δ): 3.03-3.27(6H, m), 3.80(3H, s), 5.03-5.07(1H,m), 6.38(1H, br), 6.96(1H, d, J=7.9 Hz), 7.06(1H, s), 7.29-7.48(5H, m),7.58(1H, d, J=8.3 Hz), 7.96(1H, d, J=8.3 Hz), 9.13-9.18(1H, br)

[1040] (−)ESI-MS m/z: 424 (M−HCl−H)⁻

[1041] (11)2′-Chloro-4′-[2-[[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]-1,1′-biphenyl-4-carboxylicAcid Hydrochloride

[1042] NMR (DMSO-d₆, δ): 3.00-3.27(6H, m), 5.01-5.07(1H, m),6.37-6.39(1H, br), 6.96(1H, d, J=7.9 Hz), 7.34-7.57(9H, m), 8.04(2H, d,J=8.3 Hz), 9.04-9.30(1H, br)

[1043] (−)ESI-MS m/z: 428 (M−HCl−H)⁻

[1044] (12)4′-[2-[[(2R)-2-Hydroxy-2-phenylethyl]amino]ethyl]-3-(isopropylthio)-1,1′-biphenyl-4-carboxylicAcid Hydrochloride

[1045] NMR (DMSO-d₆, δ): 1.31 (6H, d, J=6.5 Hz), 2.99-3.33 (6H, m),3.69-3.82 (1H, m), 4.96-5.00 (1H, m), 6.22 (1H, m), 7.30-7.92 (12H, m)

[1046] (−)ESI-MS m/z: 434 (M−HCl−H)⁻

[1047] (13)4′-[2-[[(2R)-2-Hydroxy-2-phenylethyl]amino]ethyl]-3-(isopropylsulfonyl)-1,1′-biphenyl-4-carboxylicAcid Hydrochloride

[1048] NMR (DMSO-d₆, δ): 1.25 (6H, d, J=6.8 Hz), 2.99-3.33 (6H, m),3.94-4.08 (1H, m), 4.96-5.00 (1H, m), 6.22 (1H, m), 7.27-8.12 (12H, m)

[1049] (−)ESI-MS m/z: 466 (M−HCl−H)⁻

EXAMPLE 41

[1050] The following compounds were obtained according to a similarmanner to that of Example 14 followed by a similar manner to that ofExample 18.

[1051] (1)4′-[2-[[(2R)-2-Hydroxy-2-phenylethyl]amino]ethyl]-3-isobutyl-1,1′-biphenyl-4-carboxylicAcid Hydrochloride

[1052] NMR (DMSO-d₆, δ): 0.89(6H, d, J=8 Hz), 1.80-2.00(1H, m),2.90-3.40(8H, m), 4.90-5.10(1H, m), 7.30-7.80(12H, m)

[1053] MS (m/z): 418 (M+H)

[1054] (2)4′-[(2R)-2-[[(2R)-2-Hydroxy-2-phenylethyl]amino]-propyl]-3-isobutyl-1,1′-biphenyl-4-carboxylicAcid Hydrochloride

[1055] NMR (DMSO-d₆, δ): 0.89(7H, d, J=6 Hz), 1.21(3H, d, J=6 Hz),1.80-1.90(1H, m), 2.70-3.60(7H, m), 5.00-5.10(1H, m), 7.20-7.80(12H, m)

[1056] MS (m/z): 432 (M+H)

[1057] (3)4′-[2-[[(2R)-2-Hydroxy-2-phenylethyl]amino]ethyl]-3-isopropyl-1,1′-biphenyl-4-carboxylicAcid Hydrochloride

[1058] NMR (DMSO-d₆, δ): 1.20(3H, d, J=7 Hz), 2.90-3.40(6H, m),3.80-3.90(1H, m), 4.90-5.00(1H, m), 7.20-7.80(12H, m)

[1059] MS (m/z): 404 (M+H)

[1060] (4)4′-[2-[[(2R)-2-Hydroxy-2-phenylethyl]amino]ethyl]-3-phenyl-1,1′-biphenyl-4-carboxylicAcid Hydrochloride

[1061] NMR (DMSO-d₆, δ): 2.90-3.40(6H, m), 4.95-5.10(1H, m),7.30-7.80(17H, m)

[1062] MS (m/z): 438 (M+H)

[1063] (5)4′-[2-[[(2R)-2-Hydroxy-2-phenylethyl]amino]ethyl]-3-propyl-1,1′-biphenyl-4-carboxylicAcid Hydrochloride

[1064] NMR (DMSO-d₆, δ): 0.90-1.05(3H, m), 1.50-1.70(2H, m),2.80-3.40(8H, m), 4.90-5.05(1H, m), 7.20-7.80(12H, m)

[1065] MS (m/z): 404 (M+H)

[1066] (6)4′-[(2R)-2-[[(2R)-2-Hydroxy-2-phenylethyl]amino]-propyl]-3-propyl-1,1′-biphenyl-4-carboxylicAcid Hydrochloride

[1067] NMR (DMSO-d₆, δ): 0.80-1.70(8H, m), 2.70-3.20(7H, m),5.00-5.15(1H, m), 7.10-7.90(12H, m)

[1068] MS (m/z): 418 (M+H)

[1069] (7)4′-[(2R)-2-[[(2R)-2-Hydroxy-2-phenylethyl]amino]-propyl]-3-isopropyl-1,1′-biphenyl-4-carboxylicAcid Hydrochloride

[1070] NMR (DMSO-d₆, δ): 1.05-1.10(9H, m), 2.05-2.15(1H, m),2.80-3.60(5H, m), 5.00-5.15(1H, m), 7.20-7.80(12H, m)

[1071] MS (m/z): 418 (M+H)

[1072] (8)4′-[(2R)-2-[[(2R)-2-Hydroxy-2-(3-pyridyl)ethyl]-amino]propyl]-3-phenyl-1,1′-biphenyl-4-carboxylicAcid dihydrochloride

[1073] NMR (DMSO-d₆, δ): 1.15(3H, d, J=6 Hz), 2.80-2.90(1H, m),3.20-3.60(4H, m), 5.10-5.20(1H, m), 7.30-7.90(13H, m), 8.30-8.40(1H, m),8.70-8.90(2H, m)

[1074] MS (m/z): 453 (M+H)

[1075] (9)4′-[2-[[(2R)-2-Hydroxy-2-phenylethyl]amino]ethyl]-3-phenyl-1,1′-biphenyl-4-carboxylicAcid Hydrochloride

[1076] NMR (DMSO-d₆, δ): 3.00-3.60(6H, m), 5.20-5.30(1H, m),7.20-7.90(13H, m), 8.30-8.40(1H, m), 8.70-8.80(2H, m)

[1077] MS (m/z): 439 (M+H)

EXAMPLE 42

[1078] The following compounds were obtained by conversion of an aminoprotective group from each corresponding amino protective group ofbenzyl in a conventional manner.

[1079] (1) Ethyl6-[4-[2-[N-(tert-butoxycarbonyl)-N-[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]phenyl]-nicotinate

[1080] (+)ESI-MS m/z: 547 (M+Na)⁺

[1081] (2) Methyl4′-[2-[N-(tert-butoxycarbonyl)-N-[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]-2,6-dimethyl-1,1′-biphenyl-4-carboxylate

[1082] (+)ESI-MS m/z: 560 (M+Na)⁺

EXAMPLE 43

[1083] The following compound was obtained according to a similar mannerto that of Example 55.

[1084] tert-ButylN-[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]-N-[2-(3′-hydroxy-1,1′-biphenyl-4-yl)ethyl]carbamate

[1085] (+)ESI-MS m/z: 468 (M+H)⁺

EXAMPLE 44

[1086] The following compound was obtained by a replacement reaction ofthe object compound of Example 43 with tert-butyl 2-bromoacetate in aconventional manner.

[1087] tert-Butyl[[4′-[2-[N-(tert-butoxycarbonyl)-N-[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]-1,1′-biphenyl-3-yl]oxy]acetate

[1088] (+)ESI-MS m/z: 582 (M+H)⁺

EXAMPLE 45

[1089] The following compound was obtained by elimination of two aminoprotective groups of the object compound of Example 44 in a conventionalmanner.[[4′-[2-[[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]-amino]ethyl]-1,1′-biphenyl-3-yl]oxy]aceticacid hydrochloride

[1090] NMR (DMSO-d₆, δ): 3.00-3.27(6H,m), 4.76(2H,s), 5.01-5.05(1H,m),6.36(1H,br), 6.90(1H,m), 7.15-7.48(9H,m), 7.64(2H,d,J=8.0 Hz),9.09-9.21(1H,br)

[1091] (−)ESI-MS m/z: 424 (M−HCl−H)⁻

EXAMPLE 46

[1092] 20 The following compound was obtained according to a similarmanner to that of Preparation 61.

[1093] Methyl4-bromo-3-[[4-[2-[N-(tert-butoxycarbonyl)-N-[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]-25phenoxy]methyl]benzoate

[1094] (+)ESI-MS m/z: 617, 619 (M+H)⁺

EXAMPLE 47

[1095] The following compound was obtained according to a 30 similarmanner to that of Example 20.

[1096] tert-ButylN-[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]-N-[2-[4′-formyl-3′-(1-piperidinyl)-1,1′-biphenyl-4-yl]ethyl]carbamate35 NMR (DMSO-d₆, δ): 1.71-2.00(6H, m), 3.09-3.20(6H,m), 3.47-3.59(4H,br), 5.06-5.10(1H, m), 7.28-7.48(6H, m), 7.82-7.89(3H, m), 8.12-8.21(2H,m)

[1097] (−)ESI-MS m/z: 474 (M−HCl−H)⁻

EXAMPLE 48

[1098] The following compound was obtained according to a similar mannerto that of Preparation 28.

[1099] Methyl3-[2-[N-(tert-butoxycarbonyl)-N-[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]-6H-benzo[c]chromene-8-carboxylate

[1100] (+)ESI-MS m/z: 538 (M+H)⁺

EXAMPLE 49

[1101] The following compound was obtained according to a similar mannerto that of Preparation 62.

[1102] Methyl2-[2-[N-(tert-butoxycarbonyl)-N-[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]-6H-benzo[c]chromene-8-carboxylate

[1103] (+)ESI-MS m/z: 560 (M+Na)⁺

EXAMPLE 50

[1104] The following compounds were obtained according to a similarmanner to that of Example 1.

[1105] (1)4′-[2-[N-(tert-Butoxycarbonyl)-N-[(2R)-2-hydroxy-2-(3-pyridyl)ethyl]amino]ethyl]-3-phenoxy-1,1′-biphenyl-4-carboxylicAcid

[1106] MS (m/z): 555 (M+H)

[1107] (2)4′-[2-[N-(tert-Butoxycarbonyl)-N-[(2R)-2-hydroxy-2-phenylethyl]amino]ethyl]-3-(1-piperidinyl)-1,1′-biphenyl-4-carboxylicAcid

[1108] MS (m/z): 545 (M+H)

EXAMPLE 51

[1109] The following compound was obtained according to a similar mannerto that of Example 1 followed by a similar manner to that of Example 25.41-[(2R)-2-[N-(tert-Butoxycarbonyl)-N-[(2R)-2-hydroxy-2-(3-pyridyl)ethyl]amino]propyl]-3-phenoxy-1,1′-biphenyl-4-carboxylicacid

[1110] MS (m/z): 569 (M+H)

EXAMPLE 52

[1111] The following compound was obtained according to a similar mannerto that of Example 25 followed by a similar manner to that of Example18.5-[4-[(2R)-2-[[(2R)-2-Hydroxy-2-(3-pyridyl)ethyl]-amino]propyl]phenyl]-1-naphthoicacid dihydrochloride

[1112] MS (m/z): 426 (M+H)

EXAMPLE 53

[1113] The following compound was obtained according to a similar mannerto that of Example 25 followed by a similar manner to that of Example27.4-[4-[(2R)-2-[[(2R)-2-Hydroxy-2-(3-pyridyl)ethyl]-amino]propyl]phenyl]-1-naphthoicacid dihydrochloride

[1114] MS (m/z): 427 (M+H)

EXAMPLE 54

[1115] The following compound was obtained according to a similar mannerto that of Example 25.

[1116] tert-ButylN-[(1R)-2-[4¹-[(benzoylamino)sulfonyl]-1,1¹-biphenyl-4-yl]-1-methylethyl]-N-[(2R)-2-hydroxy-2-(3-pyridyl)ethyl]carbamate

[1117] MS (m/z) 616 (M+H)

EXAMPLE 55

[1118] The following compound was obtained according to a similar mannerto that of Example 7.

[1119] Methyl4′-[2-[N-(tert-butoxycarbonyl)-N-[(2R)-2-hydroxy-2-pyenylethyl]amino]ethyl]-3-(isopropylthio)-1,1′-biphenyl-4-carboxylate

[1120] (+)ESI-MS (m/z): 572 (M+Na)⁺

EXAMPLE 56

[1121] To a solution of methyl4′-[2-[N-(tert-butoxycarbonyl)-N-[(2R)-2-hydroxy-2-phenylethyl]amino]ethyl]-3-(isopropylthio)-1,1′-biphenyl-4-carboxylate(338 mg) in chloroform (8 ml) and N,N-dimethylformamide (4 ml) was addedm-chloroperbenzoic acid (594 mg) at room temperature and the mixture wasstirred at the same temperature for 1 hour. To the mixture was addedwater and extracted with dichloromethane. The organic layer was washedwith brine, dried over magnesium sulfate and evaporated. The residue waspurified by column chromatography on silica gel (hexane/ethylacetate=2/1) to give methyl4′-[2-[N-(tert-butoxycarbonyl)-N-[(2R)-2-hydroxy-2-phenylethyl]amino]-ethyl]-3-(isopropylsulfonyl)-1,1′-biphenyl-4-carboxylate(340 mg).

[1122] (+)ESI-MS m/z: 604 (M+Na)⁺

[1123] Preparation 71

[1124] To a solution of(2R)-N-benzyl-N-[2-(4-bromophenyl)-ethyl]-2-[[tert-butyl(dimethyl)silyl]oxy]-2-(3-chlorophenyl)ethanamine(2.1 g) in tetrahydrofuran (25 ml) was added a solution of butyllithiumin hexane (1.59M, 2.83 ml) dropwise at −70° C. under nitrogen and themixture was stirred at −70° C. for 30 minutes. To the reaction mixturewas added 4-[[tert-butyl(dimethyl)silyl]oxy]benzaldehyde (977 mg) at−70° C., and the mixture was stirred at −70° C. for 1 hour. The mixturewas allowed to warm to room temperature and partitioned between ethylacetate and water. The organic layer was separated, washed withsaturated sodium biscarbonate solution and brine, dried over magnesiumsulfate and evaporated under reduced pressure. The residue was purifiedby column chromatography on silica gel (hexane/ethyl acetate=10/1) togive[4-[2-[N-benzyl-N-[(2R)-2-[[tert-butyl(dimethyl)silyl]oxy]-2-(3-chlorophenyl)ethyl]amino]ethyl]phenyl][4-[[tert-butyl(dimethyl)silyl]-oxy]phenyl]methanol(1.1 g).

[1125] (+)ESI-MS m/z: 716 (M+H)⁺

[1126] Preparation 72

[1127] To a solution of(1R)-2-[[2-(4-bromophenyl)ethyl]-amino]-1-(3-chlorophenyl)ethanol (5.1g) and imidazole (2.9 g) in N,N-dimethylformamide (30 ml) was addedtert-butyl(dimethyl)silyl chloride (5.85 g) and the mixture was stirredat 40° C. for 24 hours. The mixture was partitioned between ethylacetate and water. The organic layer was separated, washed with water,5% acetic acid solution, saturated sodium biscarbonate solution andbrine, dried over magnesium sulfate and evaporated under reducedpressure to give a crude product. To a solution of the product intetrahydrofuran (80 ml) and triethylamine (2.0 ml) was addeddi-tert-butyl dicarbonate (3.14 g), and the mixture was stirred at roomtemperature for 3 hours. The mixture was partitioned between ethylacetate and water. The organic layer was separated, washed with waterand brine, dried over magnesium sulfate and evaporated under reducedpressure. The residue was purified by column chromatography on silicagel (hexane/ethyl acetate=20/1) to give tert-butylN-[2-(4-bromophenyl)ethyl]-N-[(2R)-2-[[tert-butyl(dimethyl)silyl]oxy]-2-(3-chlorophenyl)ethyl]carbamate(5.0 g).

[1128] (+)ESI-MS m/z: 568 (M+H)⁺

[1129] Preparation 73

[1130] To a solution of tert-butylN-[2-(4-bromophenyl)-ethyl]-N-[(2R)-2-[[tert-butyl(dimethyl)silyl]oxy]-2-(3-chlorophenyl)ethyl]carbamate(880 mg) in tetrahydrofuran (13 ml) was added a solution of butyllithiumin hexane (1.59M, 1.07 ml) dropwise at −70° C. under nitrogen and themixture was stirred at −70° C. for 30 minutes. To the reaction mixturewas added 4-[[tert-butyl(dimethyl)silyl]oxy]-N-methoxy-N-methylbenzamide(480 mg) at −70° C., and the mixture was stirred at −70° C. for 1 hour.The mixture was allowed to warm to room temperature and partitionedbetween ethyl acetate and water. The organic layer was separated, washedwith saturated sodium bicarbonate solution and brine, dried overmagnesium sulfate and evaporated under reduced pressure. The residue waspurified by column chromatography on silica gel (hexane/ethylacetate=10/1) to give tert-butylN-[2-[4-[4-[[tert-butyl(dimethyl)silyl]oxy]benzoyl]phenyl]ethyl]-N-[(2R)-2-[[tert-butyl(dimethyl)silyl]oxy]-2-(3-chlorophenyl)ethyl]carbamate(710 mg).

[1131] (+)ESI-MS m/z: 746 (M+Na)⁺

[1132] Preparation 74

[1133] Di-tert-butyl dicarbonate (2.18 g) was added to a solution of2-(4-bromophenyl)ethanamine (2.0 g) in tetrahydrofuran (5 ml) under icewater cooling over 10 minutes and the mixture was stirred at roomtemperature for further 1 hour. The reaction mixture was evaporated invacuo to give tert-butyl 2-(4-bromophenyl)ethylcarbamate (2.98 g) as acolorless foam.

[1134] NMR (CDCl₃, δ): 1.43 (9H, s), 2.75 (2H, t, J=8 Hz), 3.36 (2H, t,J=8 Hz), 7.00-7.10 (2H, m), 7.30-7.50 (2H, m)

[1135] Preparation 75

[1136] The following compound was obtained according to a similar mannerto that of Preparation 3.

[1137] Methyl4′-[2-[(tert-butoxycarbonyl)amino]ethyl]-1,1′-biphenyl-4-carboxylate

[1138] MS m/z: 356 (M+H)

[1139] Preparation 76

[1140] The following compound was obtained according to a similar mannerto that of Example 4.

[1141] Methyl 4′-(2-aminoethyl)-1,1′-biphenyl-4-carboxylatehydrochloride

[1142] NMR (DMSO-d₆, δ): 2.80-3.10 (4H, m), 3.88 (3H, s), 7.40 (2H, d,J=8 Hz), 7.60-8.10 (6H, m)

[1143] Preparation 77

[1144] To a solution of methyl4′-(2-aminoethyl)-1,1′-biphenyl-4-carboxylate hydrochloride (420 mg) andbenzaldehyde (153 mg) in dichloromethane (5 ml) was stirred for 3 hours,and the mixture was evaporated in vacuo. To the residue in methanol (10ml) was added sodium borohydride (65 mg) on ice cooling, and stirred atthe same temperature for 1 hour. The resulting mixture was poured intosaturated aqueous sodium bicarbonate solution, and extracted with ethylacetate. The organic layer was washed with brine, dried over magnesiumsulfate, and evaporated in vacuo. The residue was chromatographed(hexane—ethyl acetate) over silica gel to afford methyl4′-[2-(benzylamino)ethyl]-1,1′-biphenyl-4-carboxylate (460 mg) as acolorless powder.

[1145] MS m/z: 346 (M+H)

[1146] Preparation 78

[1147] Under nitrogen at 4° C., to a solution of2,2,2-trifluoro-N-[2-[4-[(4-methoxyphenyl)thio]phenyl]ethyl]-acetamide(1.5 g) in dichloromethane (15 ml) was added 1M boron tribromide indichloromethane (10.5 ml), and the mixture was stirred at roomtemperature for 15 hours. The mixture was evaporated under reducedpressure. The residue was dissolved in a mixture of dichloromethane andsaturated aqueous sodium bicarbonate. After separation, the organiclayer was dried over magnesium sulfate and evaporated under reducedpressure to give2,2,2-trifluoro-N-[2-[4-[(4-hydroxyphenyl)thio]phenyl]ethyl]acetamide(1.42 g).

[1148] (+)ESI-MS m/z: 364 (M+Na)⁺

[1149] Preparation 79

[1150] To a solution of2,2,2-trifluoro-N-[2-[4-[(4-hydroxyphenyl)thio]phenyl]ethyl]acetamide(480 mg) in methanol (5.0 ml) was added 1N sodium hydroxide solution(2.8 ml). The mixture was refluxed for 12 hours. The mixture wasevaporated under reduced pressure. The residue was dissolved in amixture of dichloromethane (40 ml), 1N hydrochloric acid solution (2.0ml) and water (15 ml). After separation, the organic layer was driedover magnesium sulfate and evaporated under reduced pressure to give4-[[4-(2-aminoethyl)phenyl]thio]phenol (300 mg).

[1151] (−)ESI-MS m/z: 244 (M−H)⁻

[1152] Preparation 80

[1153] To a solution of (αS,βR)-4-hydroxynorephedrine (500 mg) and4-bromophenylethyl bromide (500 mg) in N,N-dimethylformamide (5 ml) wasadded N,N-diiospropylethylamine (0.5 ml), and the mixture was stirredfor 6 hours at 80° C. The mixture was partitioned between ethyl acetateand water. The organic layer was washed with brine, dried over magnesiumsulfate, and concentrated in vacuo. The residual oil was diluted intetrahydrofuran (10 ml). To the solution was added di-tert-butyldicarbonate (1 g) at room temperature, and the mixture was stirred atthe same temperature for 12 hours. The resulting mixture was evaporatedunder pressure and the residue was purified by column chromatography onsilica gel to give4-[2-[N-[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]-N-(tert-butyloxycarbonyl)amino]ethyl]phenylbromide (520 mg).

[1154] MS m/z: 550 (M+H)

EXAMPLE 57

[1155] To a solution of(2R)-N-benzyl-N-[2-(4-bromophenyl)-ethyl]-2-[[tert-butyl(dimethyl)silyl]oxy]-2-(3-chlorophenyl)ethanamine(850 mg) in 1,2-dimethoxyethane (9 ml) was added4-[[tert-butyl(dimethyl)silyl]oxy]-phenylboronic acid (498 mg),tetrakis(triphenylphosphine)-palladium (88 mg) and aqueous solution ofsodium carbonate (2M, 1.6 ml), and the mixture was stirred at 75° C. for10 hours under nitrogen. The mixture was diluted with ethyl acetate andwater. The organic layer was separated, washed with brine, dried overmagnesium sulfate and evaporated. To a solution of the residue intetrahydrofuran (10 ml) was added 1M tetrabutylammonium fluoride intetrahydrofuran (3.6 ml), and the mixture was stirred at roomtemperature for 8 hours under nitrogen. The mixture was partitionedbetween ethyl acetate and water. The organic layer was separated, washedwith water and brine, dried over magnesium sulfate and evaporated underreduced pressure. The residue was purified by column chromatography onsilica gel (hexane/ethyl acetate=2/1) to give4′-[2-[N-benzyl-N-[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]-1,1′-biphenyl-4-ol(540 mg).

[1156] (+)ESI-MS m/z: 458 (M+H)⁺

EXAMPLE 58

[1157] A mixture of4′-[2-[N-benzyl-N-[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]-1,1′-biphenyl-4-ol(420 mg) in 4N hydrogen chloride in ethyl acetate (1.0 ml) was stirredfor 5 minutes. The solvent was removed by evaporation. A suspension ofthe residue in ethanol (1.5 ml) and chlorobenzene (3.5 ml) washydrogenated over palladium on carbon (10% w/w, 50% wet, 10 mg) underhydrogen atmosphere for 1 hour. The catalyst was filtered off, and thefiltrate was evaporated. The residue was diluted with chloroform (40 ml)and methanol (5 ml). The organic layer was washed with saturated sodiumbiscarbonate solution and brine, dried over magnesium sulfate andevaporated under reduced pressure. To the residue was addedtetrahydrofuran (3 ml) and di-tert-butyl dicarbonate (220 mg), and themixture was stirred at room temperature for 12 hours. The mixture waspartitioned between ethyl acetate and water. The organic layer wasseparated, washed with water and brine, dried over magnesium sulfate andevaporated under reduced pressure. The residue was purified by columnchromatography on silica gel (hexane/ethyl acetate=2/1) to givetert-butyl(2R)-N-[2-(3-chlorophenyl)-2-hydroxyethyl]-N-[2-(4′-hydroxy-1,1′-biphenyl-4-yl)ethyl]carbamate(245 mg).

[1158] (+)ESI-MS m/z: 490 (M+Na)⁺

EXAMPLE 59

[1159] To a solution of tert-butyl(2R)-N-[2-(3-chlorophenyl)-2-hydroxyethyl]-N-[2-(4′-hydroxy-1,1′-biphenyl-4-yl)ethyl]carbamate(240 mg) and potassium carbonate (78 mg) in N,N-dimethylformamide (4 ml)was added tert-butyl bromoacetate (110 mg), and the mixture was stirredat room temperature for 3 hours. The mixture was partitioned betweenethyl acetate and water. The organic layer was separated, washed withwater and brine, dried over magnesium sulfate and evaporated underreduced pressure. The residue was purified by column chromatography onsilica gel (hexane/ethyl acetate=3/1) to give tert-butyl[[4′-[2-[N-(tert-butoxycarbonyl)-N-[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]-1,1′-biphenyl-4-yl]oxy]acetate(245 mg).

[1160] (+)ESI-MS m/z: 0.582 (M+H)⁺

EXAMPLE 60

[1161] The following compounds were obtained according to a similarmanner to that of Example 4.

[1162] (1)[[4′-[2-[[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]-amino]ethyl]-1,1′-biphenyl-4-yl]oxy]aceticAcid Hydrochloride

[1163] NMR (DMSO-d₆, δ): 3.02-3.35 (6H, m), 4.72 (2H, s), 5.00-5.05 (1H,m), 6.37 (1H, br), 6.99 (2H, d, J=8.7 Hz), 7.30-7.61 (10H, m), 9.04 (1H,br), 13.03 (1H, br)

[1164] (−)ESI-MS m/z: 424 (M−HCl−H)⁻

[1165] (2)[4-[4-[2-[[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]-amino]ethyl]benzoyl]phenoxy]aceticAcid Hydrochloride

[1166] NMR (DMSO-d₆ δ): 3.01-3.32 (6H, m), 4.81 (2H, s), 4.96-5.00 (1H,m), 6.35 (1H, br), 7.07 (2H, d, J=8.8 Hz), 7.35-7.47 (6H, m), 7.66-7.75(4H, m), 8.99 (1H, br)

[1167] (−)ESI-MS m/z: 452 (M−HCl−H)⁻

EXAMPLE 61

[1168] To a solution of tert-butylN-[2-(4-bromophenyl)ethyl]-N-[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]carbamate(435 mg) in 1,2-dimethoxyethane (6 ml) were added4-methoxycarbonyl-phenyl boronic acid (224 mg),tetrakis(triphenylphosphine)-palladium (55 mg) and aqueous solution ofsodium carbonate (2M, 1.0 ml), and the mixture was stirred at 80° C. for2 hours under nitrogen. The mixture was diluted with ethyl acetate andwater. The organic layer was separated, washed with brine, dried overmagnesium sulfate and evaporated under reduced pressure. The residue waspurified by column chromatography on silica gel (hexane/ethylacetate=3/1) to give methyl4′-[2-[N-(tert-butoxycarbonyl)-N-[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]-1,1′-biphenyl-4-carboxylate(400 mg).

[1169] (+)ESI-MS m/z: 510 (M+H)⁺

EXAMPLE 62

[1170] The following compound was obtained according to a similar mannerto that of Example 6.4′-[2-[[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino]-ethyl]-1,1′-biphenyl-4-carboxylicacid hydrochloride

[1171] NMR (DMSO-d₆, δ): 3.01-3.27 (6H, m), 5.01-5.06 (1H, m), 6.36 (1H,br), 7.34-7.48 (6H, m), 7.70-7.81 (6H, m), 8.02 (2H, d, J=8.4 Hz), 9.11(1H, br)

[1172] (−)ESI-MS m/z: 394 (M−HCl−H)⁻

EXAMPLE 63

[1173] To a solution of [4-[2-[N-benzyl-N-[(2R)-2-[[tert-butyl(dimethyl) silyl]oxy]-2-(3-chlorophenyl)ethyl]amino]-ethyl]phenyl][4-[[tert-butyl(dimethyl)silyl]oxy]phenyl]-methanol(1.1 g) in tetrahydrofuran (15 ml) was added 1M tetrabutylammoniumfluoride in tetrahydrofuran (5.0 ml) at 0° C., and the mixture wasstirred at room temperature for 24 hours under nitrogen. The mixture waspartitioned between ethyl acetate and water. The organic layer wasseparated, washed with water and brine, dried over magnesium sulfate andevaporated under reduced pressure. The residue was purified by columnchromatography on silica gel (hexane/ethyl acetate=2/1) to give4-[[4-[2-[N-benzyl-N-[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]-phenyl](hydroxy)methyl]phenol(550 mg).

[1174] (+)ESI-MS m/z: 486 (M−H)⁻

EXAMPLE 64

[1175] A mixture of4-[[4-[2-[N-benzyl-N-[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]phenyl](hydroxy)methyl]phenol (545 mg) in 4N hydrogen chloride in 1,4-dioxane(1.0 ml) was stirred for 5 minutes. The solvent was removed byevaporation. A suspension of the residue in ethanol (2.2 ml) andchlorobenzene (5.2 ml) was hydrogenated over palladium on carbon (10%w/w, 50% wet, 55 mg) under hydrogen atmosphere for 2 hours. The catalystwas filtered off, and the filtrate was evaporated. The residue wasdiluted with ethyl acetate and saturated sodium biscarbonate solution.The organic layer was separated, washed with brine, dried over magnesiumsulfate and evaporated under reduced pressure to give4-[4-[2-[[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]benzyl]phenol(395 mg)

[1176] (+)ESI-MS m/z: 382 (M+H)⁺

EXAMPLE 65

[1177] To a solution of4-[4-[2-[[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]benzyl]phenol(390 mg) in tetrahydrofuran (3.5 ml) and water (3.5 ml) was addeddi-tert-butyl dicarbonate (223 mg), and the mixture was stirred at roomtemperature for 30 minutes. The mixture was partitioned between ethylacetate and water. The organic layer was separated, washed with brine,dried over magnesium sulfate and evaporated under reduced pressure togive tert-butyl(2R)-N-[2-(3-chlorophenyl)-2-hydroxyethyl]-N-[2-[4-(4-hydroxybenzyl)phenyl]ethyl]carbamate(480 mg).

[1178] (+)ESI-MS m/z: 482 (M+H)⁺

EXAMPLE 66

[1179] The following compounds were obtained according to a similarmanner to that of Example 57.

[1180] (1) tert-Butyl[4-[4-[2-[N-(tert-butoxycarbonyl)-N-[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]benzyl]-phenoxy]acetate

[1181] (+)ESI-MS m/z: 598 (M+H)⁺

[1182] (2) tert-Butyl[4-[4-[2-[N-(tert-butoxycarbonyl)-N-[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]benzoyl]-phenoxy]acetate

[1183] (+)ESI-MS m/z: 610 (M+H)⁺

EXAMPLE 67

[1184] A solution of tert-butyl[4-[4-[2-[N-(tert-butoxycarbonyl)-N-[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]-amino]ethyl]benzyl]phenoxy]acetate(240 mg) and 4N hydrochloride in 1,4-dioxane (3.0 ml) was stirred atroom temperature for 24 hours. The mixture was evaporated under reducedpressure. The residue was purified by column chromatography on silicagel (methanol/acetic acid/chloroform=10/1/100) to give a product. To atetrahydrofuran (2.0 ml) solution of the product, 4N hydrogen chloridein 1,4-dioxane (1.0 ml) was added. The mixture was stirred for 5 minutesand evaporated under reduced pressure to give[4-[4-[2-[[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]benzyl]phenoxy]aceticacid hydrochloride (72 mg).

[1185] NMR (DMSO-d₆, δ): 2.91-3.24 (6H, m), 3.84 (2H, s), 4.61 (2H, s),4.94-4.99 (1H, m), 6.32 (1H, br), 6.80 (2H, d, J=8.7 Hz), 7.10-7.21 (6H,m), 7.29-7.46 (4H, m), 8.89 (1H, br)

[1186] (−)ESI-MS m/z: 438 (M−HCl−H)⁻

EXAMPLE 68

[1187] The following compound was obtained according to a similar mannerto that of Example 61.

[1188] tert-ButylN-[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]-N-[2-[4-(4-hydroxybenzoyl)phenyl]ethyl]carbamate

[1189] (+)ESI-MS m/z: 496 (M+H)⁺

EXAMPLE 69

[1190] A solution of methyl4′-[2-(benzylamino)ethyl]-1,1′-biphenyl-4-carboxylate (460 mg), and2-chloro-5-[(2R)-2-oxiranyl]pyridine (207 mg) in ethanol (10 ml) wasrefluxed for 18 hours. The mixture was evaporated in vacuo. The residuewas purified by column chromatography on silica gel(chlorofor:methanol=100:1) to give methyl4′-[2-[N-benzyl-N-[(2R)-2-(6-chloro-3-pyridyl)-2-hydroxyethyl]amino]ethyl]-1,1′-biphenyl-4-carboxylate(470 mg) as a colorless foam.

[1191] MS m/z: 501 (M+H)

EXAMPLE 70

[1192] Methyl4′-[2-[N-benzyl-N-[(2R)-2-(6-chloro-3-pyridyl)-2-hydroxyethyl]amino]ethyl]-1,1′-biphenyl-4-carboxylate(470 mg), ammonium formate (296 mg) and palladium on carbon powder (100mg) in methanol (10 ml) and water (1.0 ml) was refluxed for 30 minutes.The reaction mixture was filtrated and poured into water and extractedwith ethyl acetate. The organic layer was washed with brine, dried overmagnesium sulfate, and evaporated in vacuo. A mixture of the residue waschromatographed (chloroform-methanol) over silica gel to give methyl4′-[2-[[(2R)-2-hydroxy-2-(3-pyridyl)ethyl]-amino]ethyl]-1,1′-biphenyl-4-carboxylate(326 mg) as a colorless foam.

[1193] MS m/z: 377 (M+H)

EXAMPLE 71

[1194] At room temperature, to a solution of methyl4′-[2-[[(2R)-2-hydroxy-2-(3-pyridyl)ethyl]amino]ethyl]-1,1′-biphenyl-4-carboxylate(326 mg) in methanol was added 1N sodium hydride (0.87 ml), and themixture was stirred at the same temperature for 3 hours. The resultingmixture was evaporated under reduced pressure and dried to give sodium4-[4-[2-[[(2R)-2-hydroxy-2-(3-pyridyl)ethyl]amino]-ethyl]]-1,1′-biphenyl-4-carboxylate(220 mg) as a colorless powder.

[1195] NMR (DMSO-d₆, δ): 2.50-2.80 (6H, m), 4.70 (1H, t, J=6 Hz),7.10-7.40 (3H, m), 7.50-7.70 (5H, m), 7.90-8.00 (1H, m), 8.40-8.50 (2H,m)

[1196] MS m/z: 361 (M−H)

EXAMPLE 72

[1197] 4-[[4-(2-Aminoethyl)phenyl]thio]phenol (295 mg) and(2R)-2-(3-chlorophenyl)oxirane (186 mg) in ethanol (3.5 ml) was refluxedfor 6 hours. The mixture was evaporated. The residue was purified bycolumn chromatography on silica gel (chloroform/methanol=100/3) to give4-[[4-[2-[[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]phenyl]thio]phenol(155 mg).

[1198] (+)ESI-MS m/z: 400 (M+H)⁺

EXAMPLE 73

[1199] To a solution of tert-butylN-[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]-N-[2-[4-[(4-hydroxyphenyl)thio]phenyl]-ethyl]carbamate(195 mg) and potassium carbonate (59 mg) in N,N-dimethylformamide (3 ml)was added tert-butyl bromoacetate (84 mg), and the mixture was stirredat room temperature for 3 hours. The mixture was partitioned betweenethyl acetate and water. The organic layer was separated, washed withwater and brine, dried over magnesium sulfate and evaporated underreduced pressure. The residue was purified by column chromatography onsilica gel (hexane/ethyl acetate=3/1) to give tert-butyl[4-[[4-[2-[N-(tert-butoxycarbonyl)-N-[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]phenyl]thio]phenoxy]acetate(168 mg).

[1200] (+)ESI-MS m/z: 636 (M+Na)

1. A compound of the formula [I]:

X is bond,

 (in which R⁷ is hydrogen or lower alkyl), Y is bond, —O(CH₂)_(n)— (inwhich n is 1, 2, 3 or 4), (CH₂)_(m)— (in which m is 1, 2, 3 or 4),

Z is cyano, tetrazolyl, (benzylsulfonyl)carbamoyl, benzoylsulfamoyl,formyl, carboxy or protected carboxy, R¹ is hydrogen, lower alkyl orhalogen, R² is hydrogen or an amino protective group, R³ is hydrogen orlower alkyl, R⁴ is hydrogen or lower alkyl, R⁵ and R⁸ are eachindependently hydrogen, halogen, hydroxy, lower alkyl, lower alkenyl,lower alkoxy, hydroxy(lower)alkoxy, mono(or di or tri)halo(lower)alkoxy,lower alkoxy(lower)alkoxy, lower alkenyloxy, cyclo(lower)alkyloxy,cyclo(lower)alkyl(lower)alkoxy, benzyloxy, phenoxy, lower alkylthio,cyclo(lower)alkylthio, lower alkylsulfonyl, cyclo(lower)alkylsulfonyl,amino, mono(or di)(lower)alkylamino, mono(or di or tri)halo(lower)alkyl,cyano, piperidinyl or phenyl, R⁶ is hydrogen, lower alkyl or halogen, R⁹is hydrogen or lower alkyl, and i is 1 or 2, provided that (1) when X isbond,

 then R⁵ is not hydrogen, or (2) when i is 1,

or a salt thereof.
 2. A compound of claim 1, wherein

X is bond, —O—, —OCH₂—, —S— or

 (in which R⁷ is hydrogen or lower alkyl), Y is bond, —O—(CH₂)_(n)— (inwhich n is 1, 2, 3 or 4), —(CH₂)_(m)— (in which m is 1, 2, 3 or 4),

Z is carboxy or lower alkoxycarbonyl, R¹ is hydrogen or halogen, R² ishydrogen, R³ is hydrogen or lower alkyl, R⁴ is hydrogen, R⁵ is halogen,hydroxy, lower alkyl, lower alkoxy, hydroxy(lower)alkoxy, mono(or di ortri)halo(lower)alkoxy, lower alkoxy(lower)alkoxy, lower alkenyloxy,cyclo(lower)alkyloxy, phenoxy or phenyl, R⁶ is hydrogen, R⁸ is hydrogenor lower alkyl, R⁹ is hydrogen or lower alkyl, and i is 1 or
 2. 3. Acompound of claim 2, wherein

X is bond, —O—, —OCH₂—, —S— or

 (in which R is hydrogen or lower alkyl), Y is bond, —O—(CH₂)_(n)— (inwhich n is 1 or 2) or —(CH₂)_(m)— (in which m is 1 or 2), Z is carboxyor lower alkoxycarbonyl, R¹ is hydrogen or halogen, R² is hydrogen, R³is hydrogen or lower alkyl, R⁴ is hydrogen, R⁵ is halogen, hydroxy,lower alkyl or lower alkoxy, R⁶ is hydrogen, R⁸ is hydrogen or loweralkyl, R⁹ is hydrogen or lower alkyl, and i is
 1. 4. A compound of claim3, wherein

X is bond, Y is bond, Z is carboxy or lower alkoxycarbonyl, R¹ ishydrogen or halogen, R² is hydrogen, R³ is hydrogen or lower alkyl, R⁴is hydrogen, R⁵ is halogen, hydroxy, lower alkyl or lower alkoxy, R⁶ ishydrogen, R⁸ is hydrogen or lower alkyl, R⁹ is hydrogen or lower alkyl,and i is
 1. 5. A compound of claim 4, which selected from the groupconsisting of (1)4′-[2-[[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]-amino]ethyl]-2-methyl-1,1′-biphenyl-4-carboxylicacid, (2)4′-[(2R)-2-[[(2R)-2-Phenyl-2-hydroxyethyl]amino]-propyl]-3-methoxy-1,1′-biphenyl-4-carboxylicacid, (3)4′-[(2R)-2-[[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino]propyl]-3-isopropyloxy-1,1′-biphenyl-4-carboxylicacid, (4)4′-[2-[[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]-amino]ethyl]-3-methoxy-1,1′-biphenyl-4-carboxylicacid, (5)4′-[2-[[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]-amino]ethyl]-2,3-dimethyl-1,1′-biphenyl-4-carboxylicacid, (6)4′-[2-[[(2R)-2-Hydroxy-2-(3-pyridyl)ethyl]amino]-ethyl]-2-methyl-1,1′-biphenyl-4-carboxylicacid, (7)4′-[(2R)-2-[[(2R)-2-Hydroxy-2-(3-pyridyl)ethyl]-amino]propyl]-3-methoxy-1,1′-biphenyl-4-carboxylicacid, (8)4¹-[2-[[(2R)-2-(3-Fluorophenyl)-2-hydroxyethyl]-amino]ethyl]-3-propoxy-1,1′-biphenyl-4-carboxylicacid, (9)4′-[(2R)-2-[[(2R)-2-(3-Fluorophenyl)-2-hydroxyethyl]amino]propyl]-3-propoxy-1,1′-biphenyl-4-carboxylicacid, (10)4′-[2-[[(1S,2R)-2-Hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino]ethyl]-3-isopropoxy-1,1′-biphenyl-4-carboxylicacid, and (11)4′-[2-[[(2R)-2-Hydroxy-2-phenylethyl]amino]ethyl]-3-isobutyl-1,1′-biphenyl-4-carboxylicacid, or a pharmaceutically acceptable salt thereof.
 6. A process forpreparing a compound of claim 1, or a salt thereof, which comprises, (i)reacting a compound [II] of the formula:

 wherein R¹, R⁹ and

 are each as defined in claim 1, with a compound [III] of the formula:

 wherein

 X, Y, Z, R², R³, R⁴, R⁵, R⁶, R⁸ and i are each as defined in claim 1,or a salt thereof, to give a compound [I] of the formula:

 X, Y, Z R¹, R², R³, R⁴, R⁵, R⁶, R⁸, R⁹ and i are each as defined inclaim 1, or a salt thereof, (ii) subjecting a compound [Ia] of theformula:

 X, Y, Z, R¹, R³, R⁴, R⁵, R⁶, R⁸, R⁹ and i are each as defined in claim1, and R_(a) ² is an amino protective group, or a salt thereof, toelimination reaction of the amino protective group, to give a compound[Ib] of the

 X Y, Z, R¹, R³, R⁴, R⁵, R⁶, R⁸, R⁹ and i are each as defined in claim1, or a salt thereof, (iii) reacting a compound [IV] of the formula:

 R¹, R², R³, R⁴, R⁶, R⁹ and i are each as defined in claim 1, or a saltthereof, with a compound [V] of the formula:

 Y, Z, R⁵ and R⁸ are each as defined in claim 1, or a salt thereof, togive a compound [Ic] of the formula:

 Y, Z, R¹, R², R³, R⁴, R⁵, R⁶, R⁸ R⁹ and i are each as defined in claim1, or a salt thereof, (iv) reacting a compound [IV] of the formula:

 R¹, R², R³, R⁴, R⁶, R⁹ and i are each as defined in claim 1, or a saltthereof, with a compound [VI] of the formula:

 Y, Z, R⁵ and R⁸ are each as defined in claim 1, and X₁ is a leavinggroup, or a salt thereof, to give a compound [Ic] of the formula:

 Y, Z, R¹, R², R³, R⁴, R⁵, R⁶, R⁸, R⁹ and i are each as defined in claim1, or a salt thereof, (v) reacting a compound [VII] of the formula:

 R¹, R², R³, R⁴, R⁶, R⁹ and i are each as defined in claim 1, X₂ is aleaving group, or a salt thereof, with a compound [V] of the formula:

Y, Z, R⁵ and R⁸ are each as defined in claim 1, or a salt thereof, togive a compound [Id] of the formula:

Y, Z, R¹, R², R³, R⁴, R⁵, R⁶, R⁸ R⁹ and i are each as defined in claim1, or a salt thereof, and (vi) subjecting a compound [Ie] of theformula:

 X, Y, R¹, R³, R⁴, R⁵, R⁶, R⁸, R⁹ and i are each as defined in claim 1,R¹⁰ is lower alkyl, and R_(a) ² is an amino protective group, or a saltthereof, to deesterification reaction, to give a compound [If] of theformula:

 X, Y, R¹, R³, R⁴, R⁵, R⁶, R⁸, R⁹ and i are each as defined in claim 1,and R_(a) ² is defined above, or a salt thereof, and then subjecting thecompound [If] above to elimination reaction of amino protective group,to give a compound [Ig] of the formula:

X, Y, R¹, R³, R⁴, R⁵, R⁶, R⁸, or a salt thereof.
 7. A pharmaceuticalcomposition which comprises, as an active ingredient, a compound ofclaim 1 or a pharmaceutically acceptable salt thereof in admixture withpharmaceutically acceptable carriers or excipients.
 8. Use of a compoundof claim 1 or a pharmaceutically acceptable salt thereof for themanufacture of a medicament.
 9. A compound of claim 1 or apharmaceutically acceptable salt thereof for use as a medicament.
 10. Acompound of claim 1 or a pharmaceutically acceptable salt thereof foruse as selective β₃ adrenergic receptor agonists.
 11. A method for theprophylactic and/or the therapeutic treatment of pollakiuria or urinaryincontinence which comprises administering a compound of claim 1 or apharmaceutically acceptable salt thereof to a human being or an animal.